diff --git "a/data/test.csv" "b/data/test.csv" --- "a/data/test.csv" +++ "b/data/test.csv" @@ -1,1690 +1,1690 @@ -sentence pmcid gene1 gene2 variant1 variant2 label -(a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of @GENE$ @VARIANT$ mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type @GENE$ (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability. 8739608 SCN5A;22738 KCNH2;201 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 PAX3;22494 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons. 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane. 7067772 EphA2;20929 pendrin;20132 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. 3842385 EDA;1896 WNT10A;22525 c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 1 -In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). 6161649 SCUBE2;36383 RASA1;2168 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293 0 -We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe). 6567512 BBS7;12395 BBS6;10318 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 0 -Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROK2;9268 FGFR1;69065 p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 TYRO3;4585 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (c.965delA), @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$) genes. 7877624 SNAI2;31127 C2orf74;49849 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 1 -Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 TARDBP;7221 FUS;2521 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 0 -In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3). 6161649 TIMP3;36322 RASA1;2168 c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293 p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293 0 -Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, @GENE$ (TACR3). Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. 8152424 tachykinin receptor 3;824 CCDC88C;18903 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -Altogether, the results suggest that @GENE$ F307S is a loss-of-function mutation in Drosophila. KAT2B @VARIANT$ but not @GENE$ @VARIANT$ causes cardiac defects in Drosophila Since the presence of SRNS and heart defects in family A was the main phenotypic difference from the other families, we looked more specifically into the cardiac and renal system of the fly. 5973622 KAT2B;20834 ADD3;40893 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 0 -The proband, who had @GENE$ p.(@VARIANT$), p.(Ser127Thr), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. 8621929 LRP6;1747 WNT10A;22525 Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 1 -We identified a novel variant in BBS1 patient #10 c.1285dup (@VARIANT$) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic. A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, was identified in patient #3. BBS1, @GENE$ and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of BBS2 and BBS7 lie in this portion. The variant in @GENE$ is noteworthy, since very few Bardet-Biedl cases are reported in the literature. 6567512 BBS2;12122 BBS7;12395 p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 0 -The @GENE$-p.R583H variant was previously reported to be associated with LQTS; KCNH2-@VARIANT$ is a novel variant; and @GENE$-p.K897T and KCNE1-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels. 5578023 KCNQ1;85014 KCNH2;201 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in @GENE$, @GENE$, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. 8446458 DUSP6;55621 ANOS1;55445 Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050 Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 MITF;4892 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and @GENE$. 3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, @VARIANT$, and p.Asn1075Ser were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively. Particularly, @VARIANT$ and p.Ala754Pro were highly destabilizing, as their DeltaDeltaGs were higher than 1.00 kcal mol-1. 8621929 LRP6;1747 WNT10A;22525 p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040 0 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea. 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -This analysis indicated that the @GENE$ variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging. 6180278 CAPN3;52 DES;56469 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 0 -Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, @VARIANT$, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B). 8621929 LRP6;1747 WNT10A;22525 c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 1 -Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and @GENE$-@VARIANT$ (p.R583H) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. Primers used for mutagenesis are available upon request. The @GENE$-WT, KCNQ1-WT, and mutant coding sequences were engineered in bicistronic mammalian vectors pIRES2-EGFP (Biosciences-Clontech, Palo Alto, CA, USA). 5578023 KCNQ1;85014 KCNH2;201 c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757 c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SOX10;5055 SNAI2;31127 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; @VARIANT$, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B). 8621929 LRP6;1747 WNT10A;22525 g.112084C>G;tmVar:g|SUB|C|112084|G;HGVS:g.112084C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 1 -Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 FGFR1;69065 p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). 8152424 FGFR1;69065 DCC;21081 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 0 -Identification of the KCNQ1, @GENE$ and @GENE$ Variants We identified four variants that could influence the length of the QT interval. Variant KCNQ1-c.G1748A results in the non-conservative substitution of arginine with histidine at position 583 (@VARIANT$) located within the C-terminal domain. Since this variant was previously reported in LQTS patients and is rare in the general population (minor allele frequency (MAF) of 0.000016 in the Exome Aggregation Consortium (ExAC) database), it was initially considered a likely pathogenic mutation. Variant KCNH2-c.G323A causes the replacement of a cysteine residue by tyrosine (p.C108Y) within the N-terminal PAS (Per-Arnt-Sim) domain. Since KCNH2-@VARIANT$ had not previously been reported, we considered it to be a variant of uncertain clinical significance. 5578023 KCNH2;201 KCNE1;3753 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 0 -21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 @GENE$, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as @GENE$ induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 7689793 EBNA1BP2;4969 Calpain-9;38208 p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919 p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 0 -Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro. 4470809 TBK1;22742 OPTN;11085 p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 0 - By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous p.A194T mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL. Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of @GENE$. The pathogenic potential of the p.T123N variant is controversial. Three variants of @GENE$ (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (ANK1) identified in SH 94-208). 4998745 GJB2;2975 USH2A;66151 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399 0 -Among the 8 novel variants, 4 were classified as P (p.C176R and @VARIANT$ in @GENE$, p.T803fs in @GENE$) or LP (@VARIANT$ in DUOX2), the other were classified as VUS. 7248516 TSHR;315 DUOX2;9689 p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253 p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 TYRO3;4585 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (@VARIANT$) in MFSD8. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (EHMT1 c.1513G > A at a rate of 4.95 x 10-5, MFSD8 c. 353A > G at a rate of 8.24 x 10-6). As stated above, a heterozygous variant in @GENE$ may not result in developmental regression. 7463850 SLC9A6;55971 EHMT1;11698 c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857 p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496 0 -In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/@VARIANT$ was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). 2737700 Cx31;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Sequence alterations were detected in the @GENE$ (@VARIANT$), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and DES (rs144901249) genes. 6180278 COL6A3;37917 RYR1;68069 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 0 -In subject 10035, a deleterious variant within the @GENE$ (Chr2) locus was identified in @GENE$ (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus. 6081235 DYT21;100885773 IMP4;68891 rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628 rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415 0 -In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in @GENE$/TGF-beta signalling. 6161649 MAP4K4;7442 BMP;55955 c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022 c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 0 -Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, @VARIANT$; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B). 8621929 LRP6;1747 WNT10A;22525 p.Ser817Cys;tmVar:p|SUB|S|817|C;HGVS:p.S817C;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462 g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 1 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Finally, as regards the USH3 patients, biallelic mutations in @GENE$ and monoallelic mutations in @GENE$ or WHRN were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. 3125325 USH2A;66151 VLGR1;19815 p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795 p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406 0 -The brother who is homozygous (II.4) for the TNFRSF13B/TACI @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. 5671988 TNFRSF13B;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -KCNH2 @VARIANT$ may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A @VARIANT$ reduced the instability index of @GENE$ protein and sodium current. 8739608 Kv11.1;201 Nav1.5;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -However, this genomic @VARIANT$ variant was not seen in the NCBI SNP database or in 372 ethnically-matched controls, arguing against a polymorphism. This patient also was found to have a novel, heterozygous TACR3 nonsense mutation p.Trp275X not seen in 180 controls (Figure 1C; Table 1). @VARIANT$ lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this @GENE$, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, @GENE$, GNRHR, GNRH1, or KISS1R. 3888818 G-protein coupled receptor;3465 KAL1;55445 c.1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 Trp275;tmVar:p|Allele|W|275;VariantGroup:1;CorrespondingGene:6870;RS#:144292455 0 - Human ADD3 and KAT2B, were subcloned from human full-length cDNA (ADD3: clone IMAGE: 6649991; @GENE$ clone IMAGE: 30333414) into the expression vectors pLentiGIII and PLEX-MCS, respectively. An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and KAT2B. The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. All constructs were verified by sequencing. @GENE$ or KAT2B depleted podocytes were transduced with WT or mutant ADD3 or KAT2B lentiviral particles, respectively. 5973622 KAT2B;20834 ADD3;40893 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 0 -A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant c.1777C > G (p.Leu593Val) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. De novo variants in EHMT1 have been reported in individuals with autism, but developmental regression has not been reported. Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (@VARIANT$) in MFSD8. 7463850 SLC9A6;55971 EHMT1;11698 p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502 p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496 0 -However, none of these signs were evident from metabolic work of the patient with @GENE$ @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and NDUFS8 I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ @VARIANT$ variant in MH. 6072915 PHKA1;1981 RYR1;68069 L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635 p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146 0 -To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, @GENE$, and DFNB16, respectively. Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES. 4998745 DFNB3;56504 WFS1;4380 p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234 p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -The @VARIANT$ and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. @VARIANT$ is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The G257 and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the @GENE$ trimer. (B) The side view of the EDA trimer. Discussion This is the first study to show that simultaneous WNT10A and EDA mutations could lead to tooth agenesis in the Chinese population. We found that six participants harbored digenic mutations in both @GENE$ and EDA: two of them had isolated oligodontia and the others had syndromic tooth agenesis. 3842385 EDA;1896 WNT10A;22525 R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555 I312;tmVar:p|Allele|I|312;VariantGroup:7;CorrespondingGene:1896 0 -(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. 4998745 GJB3;7338 DFNB1;2975 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI3;8500 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 - Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of @GENE$, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. 4998745 GJB2;2975 MITF;4892 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant c.1777C > G (@VARIANT$) in SLC9A6. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. De novo variants in EHMT1 have been reported in individuals with autism, but developmental regression has not been reported. Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. 7463850 EHMT1;11698 SLC9A6;55971 p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502 p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465 0 -(A) The @GENE$ mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. 3125325 USH1C;77476 USH2A;66151 c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415 c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060 0 -RESULTS Molecular genetic testing of the RAS/MAPK pathway revealed a known pathologic heterozygous mutation in exon 12 of @GENE$ (@VARIANT$) and a novel missense variant in @GENE$ (@VARIANT$; Fig. 3). 5101836 PTPN11;2122 SOS1;4117 p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134 p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660 0 -In this family, the 40-year-old mother with heterozygous loss of both @GENE$ and @GENE$ showed mild myopathy, whereas her 8-year-old daughter with the same genotype had no muscle weakness indicating variable presentation and the possibility of later-onset clinical features. There are multiple other patient cases identified with single pathogenic variant in one recessive gene and another single VUS in a different recessive gene with no other reportable variant. Multigenic inheritance in LGMD. Pathogenic variants identified in more than one LGMD genes in two patients with unusual disease presentation and progression indicating complex inheritance patterns of LGMD. (A) Patient with homozygous variants in both ANO5 and SGCA genes. NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in ANO5 and SGCA genes, respectively. 6292381 ANO5;100071 COL6A2;1392 p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516 R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. 3842385 EDA;1896 WNT10A;22525 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. 6161649 ENG;92 VEGFR2;55639 c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). 8172206 PDGFRB;1960 SLC20A2;68531 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in @GENE$ and a de novo variant, p.R341C in @GENE$. DFNB1 as a molecular etiology was excluded from this subject, while digenic inheritance of SNHL can be proposed for this subject because the pathogenic potential of @VARIANT$ was strongly supported by significant conservation of the p.R341 residue among various species and by the absence of this variant among the 666 control chromosomes from normal hearing control subjects. 4998745 GJB2;2975 MITF;4892 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 KAL1;55445 NELF;10648 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -The NEK1 @VARIANT$ variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. @GENE$ variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. 6707335 CCNF;1335 ALS2;23264 R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 0 -It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, @VARIANT$, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed. 5611365 FOXC1;20373 PITX2;55454 p.S82T;tmVar:p|SUB|S|82|T;HGVS:p.S82T;VariantGroup:111;CorrespondingGene:6012 p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 TYRO3;4585 SNAI3;8500 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Most had C9orf72 repeat expansion combined with another mutation (e.g. VCP R155H or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in TARDBP. 5445258 TARDBP;7221 ALS2;23264 P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513 A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343 0 -(b) A sequence chromatogram showing the @GENE$ (@VARIANT$;p.R85C) mutation. (c) A sequence chromatogram showing the @GENE$ (@VARIANT$;p.I436V) mutation. 5505202 PROKR2;16368 WDR11;41229 c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601 c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 @VARIANT$, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 PTK7;43672 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 0 -"The other novel missense variant, @VARIANT$ (p.W482R), was also strongly considered pathogenic because the residue was highly conserved among various species including zebrafish and Caenorhabditis elegans as indicated by the high GERP score (6.02). This variant was predicted to be ""probably damaging"" by Polyphen2 (http://genetics.bwh.harvard.edu/pph2/) based on in silico analyses. Furthermore, this variant was not detected among the 544 control chromosomes from normal hearing Korean subjects. Similarly, SH170-377 carrying the p.V193E mutation in GJB2 also contained a previously reported homozygous @VARIANT$*36 mutant allele in Myosin XVA (@GENE$) (NM_016239) (Table 1). Although no other causative deafness mutation was detected in the initial analysis of TES data, Sanger sequencing for the low coverage area (<10x) in TES (see Table S2, Supplemental Content, which illustrates regions showing significantly low depth of coverage in TES: OTOF, STRC, and @GENE$) revealed the two known pathogenic STRC mutations as a compound heterozygous configuration in SB175-334 (Table 1)." 4998745 MYO15A;56504 OTOA;71803 c.1444T>C;tmVar:c|SUB|T|1444|C;HGVS:c.1444T>C;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956 p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043 0 -Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 DVL3;20928 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 0 -The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. 6637284 SETDB1;32157 S100A3;2223 c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 -Moreover, the MAF of @GENE$-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-p.G38S were much larger (0.187 and 0.352, respectively). KCNH2-p.@VARIANT$ is not reported in the ExAC database. 5578023 KCNQ1;85014 KCNE1;3753 R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 0 -The @VARIANT$ variant alters an amino acid that is highly conserved among vertebrates (Figure 5). Another candidate variant in @GENE$ (rs7807826) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, p.Arg687*; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. 6081235 MYH13;55780 NOS2;55473 Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011 c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 Cx31;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 - In this study, we identified nine reported gene variants, and we detected 13 novel variants: @VARIANT$(p. Ser509fs) and c.1524del A(p. Ser509fs) variants in the @GENE$ gene; @VARIANT$ and c.306G > C(p. Arg102Ser) variant in the PROK2 gene: c.963dup A (p. Glu322fs), c.1695_1696insT(p. Lys566Ter), c.580G > T(p. Gly194Cys), c.1886 T > C(p. Val629Ala), c.2147G > T(p. Gly716Val), c.1081 + 1del, c.1974_ 1977del (p. Asn659fs), and c.75_ 78del (p. Thr26fs) variants in the @GENE$ gene; and c.875 T > C (p. Ile292Thr) variant in the SEMA3A gene. 8796337 KAl1;55445 FGFR1;69065 c.1525del A;tmVar:c|DEL|1525|A;HGVS:c.1525delA;VariantGroup:13;CorrespondingGene:3730 c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675 0 -Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-TEK E103D and HA-@GENE$ @VARIANT$, respectively, was significantly diminished. 5953556 CYP1B1;68035 TEK;397 E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -Limb Girdle Muscular Dystrophy due to Digenic Inheritance of @GENE$ and @GENE$ Mutations We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (rs143445685), CAPN3 (@VARIANT$), and DES (@VARIANT$) genes. 6180278 DES;56469 CAPN3;52 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 1 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). 5953556 TEK;397 CYP1B1;68035 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Similarly, SH170-377 carrying the @VARIANT$ mutation in @GENE$ also contained a previously reported homozygous @VARIANT$*36 mutant allele in Myosin XVA (MYO15A) (NM_016239) (Table 1). Although no other causative deafness mutation was detected in the initial analysis of TES data, Sanger sequencing for the low coverage area (<10x) in TES (see Table S2, Supplemental Content, which illustrates regions showing significantly low depth of coverage in TES: OTOF, STRC, and OTOA) revealed the two known pathogenic @GENE$ mutations as a compound heterozygous configuration in SB175-334 (Table 1). 4998745 GJB2;2975 STRC;15401 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043 0 -33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (@VARIANT$) and @GENE$: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3). 8256360 PKD1;250 PKHD1;16336 c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402 p.R559W;tmVar:p|SUB|R|559|W;HGVS:p.R559W;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488 0 -Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), @GENE$ (@VARIANT$), and DES (rs144901249) genes. 6180278 RYR1;68069 CAPN3;52 rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 0 -In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and @VARIANT$ (p.Gln989Leu) in DSCAM (table 2). @GENE$ and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina. 6161649 DSCAML1;79549 DSCAM;74393 p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588 c.2966A>T;tmVar:c|SUB|A|2966|T;HGVS:c.2966A>T;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 PTK7;43672 SCRIB;44228 p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 0 -This analysis indicated that the @GENE$ variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (rs144901249), which results in a @VARIANT$ change, are both predicted to be damaging. 6180278 CAPN3;52 DES;56469 c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461 p.Thr219Ile;tmVar:p|SUB|T|219|I;HGVS:p.T219I;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118 0 -A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the @GENE$-@VARIANT$ mutation led to a decreasing L-type calcium current and the protein expression defect. 5426766 SCN5A;22738 CACNA1C;55484 p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 1 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in NRXN1 and @GENE$ contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death. 6371743 NRXN1;21005 NRXN2;86984 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ p.M170I and @GENE$ @VARIANT$ with SETX @VARIANT$ and SETX p.T14I). 4293318 VAPB;36163 TAF15;131088 p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127 p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene. 6707335 ALS2;23264 DYNC1H1;1053 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 -Three pathogenic or presumably pathogenic mutations in WHRN were detected in three patients including one USH3 patient, specifically, a novel deletion (c.737delC; @VARIANT$), and two novel missense mutations (p.S11R and @VARIANT$) that affect amino acid residues located in the N-terminal Ala/Gly/Ser-rich stretch (aa 9-31) and immediately after the PDZ2 domain, respectively (Tables 2, 3, Figure 1). Notably, these missense mutations only affect the longer whirlin isoform, which is a component of the ankle link molecular complex together with @GENE$ and @GENE$. No mutations in USH3A were detected in our series of USH patients. 3125325 VLGR1;19815 usherin;66151 p.P246fsX13;tmVar:p|FS|P|246||13;HGVS:p.P246fsX13;VariantGroup:276;CorrespondingGene:26821 p.R379W;tmVar:p|SUB|R|379|W;HGVS:p.R379W;VariantGroup:161;CorrespondingGene:25861;RS#:56059137;CA#:136858 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 DVL3;20928 PTK7;43672 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818 0 - Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. 6707335 SPG11;41614 ubiquilin-2;81830 L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 TYRO3;4585 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. 6637284 SETDB1;32157 S100A3;2223 rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant. 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 SOX10;5055 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. 6161649 ENG;92 VEGFR2;55639 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 0 -RESULTS Mutations at the gap junction proteins @GENE$ and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). 2737700 Cx26;2975 Cx31;7338 A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. 6707335 ALS2;23264 MATR3;7830 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -By contrast, @GENE$ variants @VARIANT$ and @VARIANT$ activated the @GENE$ promoter similar to wt. 5893726 GATA4;1551 CYP17;73875 Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038 Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748 0 -Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and KCNQ1-@VARIANT$ (p.R583H) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously. 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -An HA tag was added in frame, before the stop codon, to the C terminus of @GENE$ and @GENE$. The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. 5973622 ADD3;40893 KAT2B;20834 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 0 -The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the @GENE$/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin. 5671988 TCF3;2408 TNFRSF13B;49320 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 - Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, @VARIANT$) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS. 8621929 WNT10A;22525 LRP6;1747 p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 0 -Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (p.N382S/@VARIANT$) and @GENE$ (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1. 7026993 GFI1;3854 MYO6;56417 c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872 c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203 0 -Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, @VARIANT$), @GENE$ p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). 8739608 SCN5A;22738 LAMA2;37306 c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099 0 -"The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys." 3842385 WNT10A;22525 EDA;1896 p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 0 -Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation. Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2). 6707335 SQSTM1;31202 KIF5A;55861 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. 3125325 MYO7A;219 USH2A;66151 c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 MITF;4892 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 Cx26;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -R583H variant was previously reported to be associated with LQTS; @GENE$-p.C108Y is a novel variant; and KCNH2-@VARIANT$ and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels. 5578023 KCNH2;201 KCNE1;3753 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). 5953556 CYP1B1;68035 TEK;397 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 1 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6. 6610752 LQT6;71688 LQT2;201 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 0 -This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and WNT10A mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. 8621929 LRP6;1747 WNT10A;22525 Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 0 -The SEMA7A gene variant was predicted as a VUS according to Varsome, whereas the @GENE$ gene variation was classified as benign. The SEMA7A variant [p.(Glu436Lys)] was absent in the 92 exomes of our local database (Supplementary Table 8). The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, DCC, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant p.(Lys205del). The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 PLXNA1;56426 SEMA7A;2678 p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for @VARIANT$. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by @GENE$ (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, @GENE$, or KISS1R. 3888818 KAL1;55445 GNRH1;641 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with @GENE$ p.I2547T and SETX p.T14I). 4293318 SOD1;392 SETX;41003 p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459 p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390 0 -c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the S100A3 protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts. 6637284 S100A13;7523 S100A3;2223 arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 -"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys." 3842385 EDA;1896 WNT10A;22525 termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes. The two mutations were in cis configuration, inherited together on the same chromosome from her father (Figure 1b). The identification of fragment deletions in @GENE$. (a) The PCR quantification results of IID5. 6565573 COL4A4;20071 COL4A5;133559 Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286 0 -The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). 4998745 GJB2;2975 GJB6;4936 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 0 -Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (@VARIANT$, p.G505D). A novel missense mutation was found in DUOXA2 (c.398G>A, @VARIANT$). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, p.H678R and p.S1067L, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001). 6098846 TG;2430 DUOX2;9689 c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370 p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341 0 -It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies. 5725008 SCAP;8160 AGXT2;12887 c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937 c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745 0 -Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 KAL1;55445 FGFR1;69065 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 TACR3;824 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -We observed that recombinant @GENE$ and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (@VARIANT$)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (@VARIANT$) exhibit perturbed interaction. 5953556 TEK;397 CYP1B1;68035 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 0 -A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene. The GNRHR frameshift mutation was identified in two different families and has not been reported before. It consists of an 11 base-pair deletion (@VARIANT$), and if translated, would be expected to result in a truncated protein due to a premature termination codon (p.Phe313Metfs*3). 5527354 GNRHR;350 PROKR2;16368 p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400 c.937_947delTTTTTAAACCC;tmVar:c|DEL|937_947|TTTTTAAACCC;HGVS:c.937_947delTTTTTAAACCC;VariantGroup:7;CorrespondingGene:2798 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Structural changes caused by both the p.Pro226Leu and p@VARIANT$ variations were not predicted to be disruptive and core GATA4 structure was not altered. Since the changes were in the DNA interaction sites, it is expected that both @VARIANT$ and pTrp228Cys mutations could have altered binding and activation of some of @GENE$ interaction partners and could also bind to other promoters and potentially change the transcription of several other genes. In fact, we found segregating genetic variants besides GATA4 in cases 2 and 3 using NGS. In one 46,XY DSD subject without CHD, a heterozygote variant in @GENE$ gene was found. 5893726 GATA4;1551 LRP4;17964 Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038 p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. 3842385 WNT10A;22525 EDA;1896 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and @VARIANT$) or reported at rare frequencies (p.Gln106Arg, at 0.2%; p.Val134Gly, at 0.0008%; p.Arg262Gln at 0.2%; and PROKR2 @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/@GENE$) heterozygous mutation. 5527354 GNRHR;350 PROKR2;16368 p.Tyr283His;tmVar:p|SUB|Y|283|H;HGVS:p.Y283H;VariantGroup:8;CorrespondingGene:2798;RS#:1237982349 p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400 0 -Heterozygous missense mutations in CELSR1 gene have previously been reported in a number of NTD patients.38, 39, 40 Two novel and 3 rare @GENE$ missense variants were identified in 5 anencephaly cases (Table 1 and Table S2 in Appendix S3). SCRIB mutations have previously been implicated in human craniorachischisis.40 Three samples carried more than 1 variant within the same gene: sample 01F292 had 2 rare @GENE$ variants (c.739C>A; @VARIANT$), f11-278 had 1 novel (@VARIANT$) and 1 rare (c.5587C>T) variants in CELSR3 and 693F06 had 2 rare missense variants (c.3109G>C; c.824G>A) in NOS2. 5887939 SCRIB;44228 FAT4;14377 c.6607C>T;tmVar:c|SUB|C|6607|T;HGVS:c.6607C>T;VariantGroup:38;CorrespondingGene:79633;RS#:374328795;CA#:3072948 c.8335C>G;tmVar:c|SUB|C|8335|G;HGVS:c.8335C>G;VariantGroup:17;CorrespondingGene:1951 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 MITF;4892 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$). 4293318 VAPB;36163 SETX;41003 p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953 p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953 0 -In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (@VARIANT$), SNAI2 (c.607C>T) and @GENE$ (@VARIANT$) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family. 7877624 C2orf74;49849 SNAI2;31127 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 0 -Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and @GENE$ (@VARIANT$), both sarcomeric genes. 6359299 MYBPC3;215 TNNT2;68050 L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954 Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235 0 -Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in @GENE$ (c.A2107C, @VARIANT$, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). 5765430 NR5A1;3638 ZFPM2;8008 p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681 p.Met703Leu;tmVar:p|SUB|M|703|L;HGVS:p.M703L;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963 1 -Sequence alterations were detected in the @GENE$ (rs144651558), RYR1 (rs143445685), @GENE$ (@VARIANT$), and DES (@VARIANT$) genes. 6180278 COL6A3;37917 CAPN3;52 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 0 -In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). 6161649 ENG;92 SCUBE2;36383 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 1 -One missense mutation (@VARIANT$) was found in the major subunit of the L-type calcium channel gene @GENE$ by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. 5426766 CACNA1C;55484 SCN5A;22738 p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 1 -This study provides additional evidence that @GENE$ missense variants may contribute to the development of sALS. Missense variants in the NEFH gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. 6707335 NEK1;14376 GRN;1577 T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 0 -A, The pedigree shows the coinheritance of the monoallelic variants which encode @GENE$ @VARIANT$ and MUTYH p.Tyr179Cys in a family affected by colorectal cancer. All spouses were unrelated and unaffected by cancer. Genotypes: MSH6 p.Thr1100Met (T1100M; blue); @GENE$ @VARIANT$ (Y179C; green); -, wild type. 7689793 MSH6;149 MUTYH;8156 p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473 p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475 0 -Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23A@VARIANT$/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.1200G>C/+ MAN1B1c.1000C>T/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.1200G>C; MAN1B1@VARIANT$/c.1000C>T (N = 328) 328 (100***) 2 (0.6***) Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone. 4853519 SEC23A;4642 MAN1B1;5230 c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. 6707335 ALS2;23264 MATR3;7830 R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene. 6707335 SPG11;41614 UBQLN2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941 0 -Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the @VARIANT$ mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism. 4470809 OPTN;11085 TBK1;22742 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 DVL3;20928 SCRIB;44228 p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026 p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 TACR3;824 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 0 -DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and @GENE$ mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed. 3842385 EDA;1896 WNT10A;22525 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). 4998745 gap junction protein beta 2;2975 GJB6;4936 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. 6637284 ISG20L2;12814 S100A3;2223 c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or @VARIANT$ (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on @GENE$ interaction and internalization was examined. 7067772 pendrin;20132 EphA2;20929 Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777 Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 0 -Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 - @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene. 6707335 MATR3;7830 DYNC1H1;1053 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). 2737700 Cx31;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Finally, as regards the USH3 patients, biallelic mutations in USH2A and monoallelic mutations in VLGR1 or @GENE$ were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. 3125325 WHRN;18739 MYO7A;219 p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795 p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. 6707335 SPG11;41614 UBQLN2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNQ1;85014 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -No mutations in @GENE$, @GENE$, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (@VARIANT$) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient. 6098846 SLC5A5;37311 TPO;461 p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915 p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391 0 - Molecular Data All three probands carry two heterozygous variants: SQSTM1, @VARIANT$ (p.Pro392Leu), and TIA1, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and @GENE$ variants have been reported in multiple databases. 5868303 TIA1;20692 SQSTM1;31202 c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A. 3125325 MYO7A;219 USH1C;77476 c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); @GENE$-@VARIANT$ and @GENE$-@VARIANT$. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. 5954460 LAMA5;4060 COL4A5;133559 p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875 p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060 1 -Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and @GENE$-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 - In a second example, we identified a monoallelic change in SRD5A2 (@VARIANT$, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of @GENE$, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014). 5765430 SF1;138518 SRD5A2;37292 c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442 single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536 0 -"Sanger sequencing was further performed for validation of the identified variants and analysis of their segregation within each family, using corresponding primer sets for @GENE$ and WNT10A. For numbering gDNA and cDNA mutation positions, the subject's sequence variants were compared to human reference sequences NG_016168.2 and NM_002336.3 for LRP6 and NG_012179.1 and NM_025216.3 for @GENE$. 2.3. Prediction of Structural Alterations Caused by LRP6 Mutations To investigate the potential impact of the identified LRP6 missense mutations on protein structure we conducted computational predictions using PremPS, recently developed software that has been shown to outperform currently available methods. For prediction of p.Ser127Thr and p.Met168Arg the PDB (Protein Data Bank) structure of 3S94 was used, which constituted a crystal structure of the human LRP6 extracellular domain (E1E2). On the other hand, 4A0P, the crystal structure of LRP6-E3E4, was employed for prediction of @VARIANT$, p.Ser817Cys, and @VARIANT$. ""A chain"" was selected in all predictions, and mutation specified manually." 8621929 LRP6;1747 WNT10A;22525 p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 0 -Immunocomplex of myc-pendrin L117F, @VARIANT$ and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by @GENE$ stimulation. 7067772 EphA2;20929 ephrin-B2;3019 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Moreover, the presence of other variants (@GENE$-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNQ1;85014 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare @GENE$ missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A). 5887939 CELSR2;1078 FAT4;14377 c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SOX10;5055 SNAI2;31127 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 - Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the @VARIANT$ variant of GJB2. The pathogenic potential of the p.T123N variant is controversial. Three variants of USH2A (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and Ankyrin 1 (@GENE$) identified in SH 94-208). 4998745 USH2A;66151 ANK1;55427 p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964 R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare @GENE$ (GLDC) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (@VARIANT$; p.Val2517Met) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (CELSR1) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3). 5887939 MTHFR;4349 glycine decarboxylase;141 c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990 c.7549G>A;tmVar:c|SUB|G|7549|A;HGVS:c.7549G>A;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6). 6610752 LQT2;201 KCNE2;71688 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 1 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). 2737700 Cx26;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. 6707335 SPG11;41614 UBQLN2;81830 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 0 -Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) PCCB G407RfrTer14; 3) NUBPL IVS8DC; 4) @GENE$ @VARIANT$. Two additional variants, p. T4823 M in @GENE$ and @VARIANT$ in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively. 6072915 OAT;231 RYR1;68069 Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942 p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268 0 -On the other hand, the WNT10A p.(@VARIANT$) mutation has been shown to cause hypodontia or no tooth agenesis in heterozygous carriers. The mother who passed this mutation had a full set of permanent dentition except for maxillary third molars. However, when combined with the LRP6 mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(@VARIANT$), p.(Ser127Thr), and WNT10A p.(Glu167Gln) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. 8621929 LRP6;1747 WNT10A;22525 Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 0 -Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes. 6565573 COL4A5;133559 COL4A4;20071 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286 0 -Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 MITF;4892 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 MITF;4892 SNAI2;31127 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and @GENE$ F355L mutations on EphA2 interaction and internalization was examined. 7067772 EphA2;20929 pendrin;20132 Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -20 The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include @GENE$, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21 @GENE$ promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 7689793 RYR3;68151 TRIP6;37757 p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849 c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls. 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-@VARIANT$ and @GENE$-@VARIANT$. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the @GENE$ have been reported in patients with focal segmental glomerulosclerosis. 5954460 COL4A5;133559 LAMA5;4060 p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875 p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060 0 -Mutagenesis Sequence variants @GENE$-@VARIANT$ (p.C108Y) and KCNQ1-@VARIANT$ (p.R583H) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously. 5578023 KCNH2;201 KCNQ1;85014 c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757 c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -Both the aborted foetuses carried the compound heterozygous pathogenic variants, namely @GENE$: @VARIANT$ and PKD1: c.7583A > G (p.Y2528C) from each parent, and these variants were inferred to have contributed to the foetal PKD. 33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the PKD1: c.4343C > T (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (p.R559W) and PKHD1: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3). 8256360 PKD1;250 PKHD1;16336 c.1386-2A > G;tmVar:c|SUB|A|1386-2|G;HGVS:c.1386-2A>G;VariantGroup:41;CorrespondingGene:5310 c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529 0 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 KAL1;55445 PROKR2;16368 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 0 -This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). 6161649 ENG;92 VEGFR2;55639 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745 0 -25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: @VARIANT$, p.Glu274Asp) and the @GENE$ (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 7689793 TRIP6;37757 CAPN9;38208 c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675 c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 0 -GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-@GENE$ proteins @VARIANT$ and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ A115P and R368H showed perturbed interaction with HA-TEK. 5953556 TEK;397 CYP1B1;68035 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2. 5671988 TCF3;2408 TACI;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered. A genetic cause was sought in a child with combined multiple pituitary hormone deficiencies. The findings implicate a digenic mechanism of inheritance, with a mutation in @GENE$ and in @GENE$. Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland that is characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic or absent posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland. 5505202 PROKR2;16368 WDR11;41229 c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601 p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 1 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3). 3888818 KAL1;55445 NELF;10648 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, @GENE$, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well. 7877624 SNAI3;8500 LRP4;17964 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 - Quantitation of epistatic interactions of TCF3 and @GENE$ mutations showing a greater net effect than the sum of each individual mutation. Total Serum Ig, clinical score and TNFRSF13B/TACI @VARIANT$ and @GENE$ @VARIANT$ genotype for each family member, as indicated. 5671988 TACI;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T161fsX191;tmVar:p|FS|T|161||191;HGVS:p.T161fsX191;VariantGroup:5;CorrespondingGene:6929 0 -Genotypes: @GENE$ @VARIANT$ (T1100M; blue); @GENE$ p.Tyr179Cys (@VARIANT$; green); -, wild type. 7689793 MSH6;149 MUTYH;8156 p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473 Y179C;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475 0 -The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and @GENE$/TACI @VARIANT$ mutations are shown. 5671988 TCF3;2408 TNFRSF13B;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -The four other variants (CELSR1 p.Q2924H, @GENE$ @VARIANT$ and @GENE$ @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2). 5966321 CELSR1;7665 SCRIB;44228 p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078 p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813 0 -Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, @GENE$, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. 8446458 SEMA7A;2678 DCC;21081 Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050 Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 0 -(a, b) Compared with wild-type @GENE$, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 @VARIANT$ showed a decreasing trend in molecular weight and increasing instability. However, the prediction of theoretical pI, aliphatic index and GRAVY presented no significant differences. Compared to the Nav1.5 protein properties of wild-type SCN5A, SCN5A p.R1865H slightly increased its molecular weight and aliphatic index but reduced its instability index. Theoretical pI, aliphatic index, and GRAVY were not affected by @GENE$ p.R1865H. 8739608 KCNH2;201 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 Cx31;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -A rare variant in @GENE$, c.428C>T; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel @GENE$ Variants To study the impact of the three novel missense variants of NR5A1 on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant NR5A1 expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel NR5A1 variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the His24Leu and @VARIANT$ variants when using the reporters for CYP11A1 and HSD17B3 (Figure 2B,C). 7696449 AMH;68060 NR5A1;3638 p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935 Cys30Ser;tmVar:p|SUB|C|30|S;HGVS:p.C30S;VariantGroup:5;CorrespondingGene:6662;RS#:1003847603;CA#:293780979 0 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087 P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866 0 -The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), R5143C, C4870F, and @VARIANT$ with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and @GENE$ (ANK1) identified in SH 94-208). 4998745 USH2A;66151 Ankyrin 1;55427 p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964 G805A;tmVar:c|SUB|G|805|A;HGVS:c.805G>A;VariantGroup:14;CorrespondingGene:7399;RS#:587783023;CA#:270788 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. 3842385 WNT10A;22525 EDA;1896 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 VAPB;36163 FUS;2521 p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 0 -This analysis indicated that the CAPN3 variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the DES gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient. 6180278 CAPN3;52 DES;56469 c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461 c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118 1 -The proband is heterozygous for the TNFRSF13B/@GENE$ @VARIANT$ mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (@VARIANT$) in the Transcription Factor 3 (@GENE$) gene encoding the E2A transcription factors, present only in the proband and her son. 5671988 TACI;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 1 -SCUBE2 forms a complex with VEGF and @GENE$ and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. 6161649 VEGFR2;55639 SCUBE2;36383 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). 2737700 Cx31;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 PAX3;22494 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 - Molecular Data All three probands carry two heterozygous variants: SQSTM1, @VARIANT$ (p.Pro392Leu), and @GENE$, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The TIA1 variant and @GENE$ variants have been reported in multiple databases. 5868303 TIA1;20692 SQSTM1;31202 c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 0 -The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and HNF4A R80Q. Both mutations are novel and whilst a different mutation, @VARIANT$, has been reported in @GENE$, further evidence to support the pathogenicity of E508K is lacking. 4090307 HNF1A;459 HNF4A;395 E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173 R80W;tmVar:p|SUB|R|80|W;HGVS:p.R80W;VariantGroup:2;CorrespondingGene:3172 0 - Recently, Gifford et al., identified three missense variants in MKL2 (Gln670His), @GENE$ (@VARIANT$), and @GENE$ (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019). 7057083 MYH7;68044 NKX2-5;1482;4824 Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625 Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2). 5966321 DVL3;20928 SCRIB;44228 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813 0 -The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). 3842385 EDA;1896 WNT10A;22525 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 1 -Moreover, patients carrying a LAMA4 @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in @GENE$ play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and MYBPC3 (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and @GENE$ (Asn83His), both sarcomeric genes. 6359299 LAMA4;37604 TNNT2;68050 Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749 L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954 0 - In the patient with the monoallelic mutation in exon 1 (@VARIANT$), additional studies were carried out to search for further genetic defects. A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene. 5527354 GNRHR;350 PROKR2;16368 p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946 p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400 1 - Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (@VARIANT$, p.Q1916R) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that Q1916 is highly conserved across mammals (red font). (C) Topology model of the alpha-subunit of LTCC. The localization of the mutation is indicated by a red dot, and polymorphisms are indicated by green dots. (D) A variant (c.3578G>A, @VARIANT$) in SCN5A. 5426766 CACNA1C;55484 SCN5A;22738 c.5747A>G;tmVar:c|SUB|A|5747|G;HGVS:c.5747A>G;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 1 -Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare @GENE$ missense variant @VARIANT$ and a novel @GENE$ missense variant c.10147G>A). 5887939 FZD1;20750 FAT4;14377 c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776 c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060 0 -PREX2 activates PI3K signalling via inhibition of phosphatase and tensin homolog (@GENE$), and both germline and mosaic PTEN variants are associated with AVMs. In patient AVM427, the de novo heterozygous missense variant @VARIANT$ (p.Asp1148Tyr) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to @GENE$-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (@VARIANT$), in EGFR (table 1). 6161649 PTEN;265 Smad1;21196 c.3442G>T;tmVar:c|SUB|G|3442|T;HGVS:c.3442G>T;VariantGroup:3;CorrespondingGene:9765 p.Glu631Ter;tmVar:p|SUB|E|631|X;HGVS:p.E631X;VariantGroup:8;RS#:909905659 0 -This and our previous study reveal a higher than expected by chance frequency of rare @GENE$ and FOXC1 variants in the analysed cohort of PCG patients (6% and 7.5%, respectively), with either experimentally assessed or inferred moderate functional defects. Segregation analysis of these variants, which were present in the heterozygous state, rule out a monogenic inheritance pattern, indicating according to our earlier reports, that these genetic changes might be involved in either oligogenic or complex transmission of the disease. Moreover, the existence of incomplete penetrance, variable expressivity and of a relatively high proportion (close to 20%) of PCG patients with rare heterozygous @GENE$ variants also suggest non-Mendelian PCG transmission in some cases. In these patients, disease outcome might depend on modifier factors (genetic, stochastic and/or environmental), as will be discussed later. Functional impact of the rare variants The two missense FOXC2 variants (p.(H395N) and (@VARIANT$) and one of the PITX2 amino acid substitutions (@VARIANT$) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation. 6338360 FOXC2;21091 CYP1B1;68035 p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. 2737700 Cx31;7338 GJB2;2975 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3). 3888818 NELF;10648 KAL1;55445 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 0 -Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (@VARIANT$), @GENE$ (rs138172448), and DES (rs144901249) genes. 6180278 COL6A3;37917 CAPN3;52 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685 0 -The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 1 -In patient AVM028, the de novo heterozygous missense variant c.311T>C (@VARIANT$), in the functional inhibition of zinc metalloproteinases (NTR) domain, was identified in TIMP3 (table 1), which encodes a tissue metalloproteinase inhibitor. @GENE$ inhibits VEGF-mediated angiogenesis by blocking VEGF/VEGFR2 binding (figure 3), a function considered independent of metalloproteinase inhibition and unique to TIMP3 compared with other known TIMPs. In patient AVM359, the de novo heterozygous missense variant c.1592G>A (@VARIANT$) was identified in SCUBE2 (table 1), which encodes a membrane-associated multidomain protein. The variant is predicted to affect a conserved site (SIFT=0, PolyPhen2=1, GERP++=5.68, CADD=24.6). SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (p.Cys531Tyr) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. 6161649 TIMP3;36322 SCUBE2;36383 p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 0 -"This sequence variant changes a glutamine codon (CAG) to a translation termination codon (TAG) at position 1252 (NP_002327.2:@VARIANT$) and will likely subject the altered transcript to nonsense mediated decay. The mutation is not documented in the Genome Aggregation Database (gnomAD) or the Taiwan BioBank database. In addition, a missense sequence variant in WNT10A (NG_012179.1:g.6853G>A; NM_025216.3:@VARIANT$; NP_079492.2:p.Arg113His) was also identified (Figure S1A). This variant, designated as rs749324327, has a minor allele frequency (MAF) of ~0.0004 in East Asian (EAS) populations and is predicted to be ""benign"", with a PolyPhen-2 score of 0.015. No potential pathogenic mutations were detected in other candidate genes of FTA. Further Sanger sequencing and segregation analysis indicated that the @GENE$ and @GENE$ mutations were both inherited from the father." 8621929 LRP6;1747 WNT10A;22525 p.Gln1252*;tmVar:p|SUB|Q|1252|*;HGVS:p.Q1252*;VariantGroup:15;CorrespondingGene:4040 c.338G>A;tmVar:c|SUB|G|338|A;HGVS:c.338G>A;VariantGroup:3;CorrespondingGene:80326;RS#:749324327;CA#:2113880 1 -To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic @GENE$ p.T511M and SLC26A4 @VARIANT$ mutations. 7067772 pendrin;20132 EPHA2;20929 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403 0 -Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 TEK;397 CYP1B1;68035 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 0 -To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations. 7067772 pendrin;20132 EphA2;20929 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403 0 -Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 TRPV4;11003 UNC13B;31376 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -The latter individuals were also carriers of the @GENE$ nonsense mutation @VARIANT$. Specifically, the mother and her twin sister were heterozygous for the @GENE$ missense mutation @VARIANT$ and the ABCC6 nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings. 2900916 ABCC6;55559 GGCX;639 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees. 6081235 GNA14;68386 MRPL15;32210 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the @GENE$ gene in fALS and sALS patients, suggesting its role in ALS. 6707335 MATR3;7830 DYNC1H1;1053 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778 0 - Mutation detection in the family (a) Identification of the recurrent nonsense mutation p.R1141X in the @GENE$ gene. Note the heterozygous @VARIANT$ transition substitution at nucleotide position 3421 (arrow). (b, d) Identification of missense mutations p.V255M and @VARIANT$ in the @GENE$ gene. 2900916 ABCC6;55559 GGCX;639 C T;tmVar:c|Allele|CT|;VariantGroup:26;CorrespondingGene:368 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 -We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric Cx26/Cx31 connexons. Furthermore, by cotransfection of mCherry-tagged Cx26 and GFP-tagged @GENE$ in human embryonic kidney-293 cells, we demonstrated that the two connexins were able to co-assemble in vitro in the same junction plaque. 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare @GENE$ (GLDC) @VARIANT$ missense variant, possibly indicating a compromised FOCM in this patient. 5887939 MTHFR;4349 glycine decarboxylase;141 c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990 c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332 1 -In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519 R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea. 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Moderate iodine deficiency in association with double heterozygosity for @GENE$ and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). 5587079 DUOX1;68136 DUOX2;9689 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026 1 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and @VARIANT$ (c.1051 G > A p.G351R), have already been described in the literature. 3975370 NOD2;11156 IL10RA;1196 2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 rs2229113;tmVar:rs2229113;VariantGroup:0;CorrespondingGene:3587;RS#:2229113 0 -In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental @GENE$-@VARIANT$ mutation might be partly compensated by the persistent inward tail INa produced by the @GENE$-@VARIANT$ channel. 5426766 CACNA1C;55484 SCN5A;22738 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 1 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 PROK2;9268 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDNRB;89 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons. 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Given the reported normal function of pendrin L117F and @GENE$ S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations. 7067772 pendrin;20132 EphA2;20929 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDNRB;89 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 SOX10;5055 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. 6161649 SCUBE2;36383 VEGFR2;55639 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 0 -These phenotypes were specific, since coinjection of nonmutant human RNF216 or @GENE$ mRNA rescued all phenotypes (Fig. 3, and Fig. S4 in the Supplementary Appendix). @GENE$ mRNA encoding @VARIANT$ and OTUD4 mRNA encoding @VARIANT$ were less effective in rescuing the phenotypes induced by double-MO injection (Fig. 3, and Fig. S4 in the Supplementary Appendix), suggesting not only that these mutant alleles encode functionally deficient proteins but also that epistatic interactions between these mutations contribute to the disease phenotype in the index pedigree. 3738065 OTUD4;35370 RNF216;19442 R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853 G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858 0 -Notably, not all @GENE$-@VARIANT$ carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by SCN5A-R1193Q variant and sex. As shown in Table 3, all male individuals carrying the CACNA1C-Q1916R mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant @GENE$-@VARIANT$ showed the ERS phenotypes. 5426766 CACNA1C;55484 SCN5A;22738 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 0 -In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 Cx26;2975 GJB3;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 PROK2;9268 p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 0 - Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein. 6707335 SPG11;41614 FUS;2521 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 - In a second example, we identified a monoallelic change in @GENE$ (c.G680A, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014). Additionally, the @VARIANT$ SRD5A2 change has been previously found to be causative of micropenis, where it was found in compound heterozygosity or homozygosity in three individuals (Sasaki et al., 2003). 5765430 SRD5A2;37292 SF1;138518 single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536 p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681 0 -No significant change was observed with HA-TEK @VARIANT$ with GFP-@GENE$ @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). 5953556 CYP1B1;68035 TEK;397 G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 0 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 KAL1;55445 FGFR1;69065 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after @GENE$ stimulation while EphA2 and other mutated pendrins were not affected. f Relative amount of cell surface pendrin is shown. Mean +- SEM; one-way ANOVA; **p < 0.01; *p < 0.05; (n = 3). Source data are provided as a Source Data file. Several amino-acid substitutions of pendrin have been identified from Pendred syndrome patients as well as non-syndromic hearing loss patients with EVA. To gain further insight into the relationship between @GENE$ and pendrin, we examined the interaction of pathogenic forms of pendrin with EphA2. 7067772 ephrin-B2;3019 EphA2;20929 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 PAX3;22494 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -By contrast, the expression of human @GENE$ and @GENE$, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, F307, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 @VARIANT$). As a negative control, we re-expressed a predicted potentially damaging KAT2B variant (@VARIANT$ corresponding to Gcn5 S478F) found in a homozygous state in a healthy individual from our in-house database. 5973622 KAT2A;41343 KAT2B;20834 F304S;tmVar:p|SUB|F|304|S;HGVS:p.F304S;VariantGroup:6;CorrespondingGene:39431 S502F;tmVar:p|SUB|S|502|F;HGVS:p.S502F;VariantGroup:3;CorrespondingGene:8850;RS#:141445570;CA#:2284662 0 -"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -It should be noted that the mother and her twin sister were heterozygous for one of the GGCX missense mutation @VARIANT$ and one ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. The occurrence of digenic inheritance, although rare, is well established (see e.g.,). The chance of a combination of mutations in the @GENE$ and @GENE$ genes is difficult to calculate, since the precise carrier frequency of the mutations in these genes is not known. 2900916 ABCC6;55559 GGCX;639 p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 1 -In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 GJB6;4936 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 @GENE$, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25 The contribution of the genetic variants, other than @GENE$ and MUTYH, to cancer risk cannot be completely excluded. 7689793 TRIP6;37757 MSH6;149 p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919 c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 0 -None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a). The @GENE$ variant [NM_033056: @VARIANT$; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892). 6053831 USH1G;56113 PCDH15;23401 55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217 c.3101G > A;tmVar:c|SUB|G|3101|A;HGVS:c.3101G>A;VariantGroup:2;CorrespondingGene:124590 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1). 5953556 TEK;397 CYP1B1;68035 p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving @GENE$, @GENE$, DCC, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant @VARIANT$. The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. 8446458 DUSP6;55621 ANOS1;55445 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 0 -The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the GGCX gene (@VARIANT$) yet did not display any cutaneous findings are not clear. Specifically, while both @GENE$ mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the p.S300F mutation was more pronounced than that of p.V255M. 2900916 ABCC6;55559 GGCX;639 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 MITF;4892 SOX10;5055 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and @GENE$. The @GENE$ @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. 5973622 KAT2B;20834 ADD3;40893 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 0 -Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, @GENE$ (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. 8152424 tachykinin receptor 3;824 FGFR1;69065 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes. 6565573 COL4A5;133559 COL4A4;20071 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3). 3888818 TACR3;824 NELF;10648 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L @GENE$ proteins, respectively (figure 2D, E). 7279190 TTC26;11786 FLNB;37480 p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058 p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246 0 -GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-@GENE$ @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). 5953556 CYP1B1;68035 TEK;397 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (@GENE$ @VARIANT$ and SCRIB c.3979G>A). 5887939 DVL3;20928 CELSR1;7665 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation. 6610752 KCNE2;71688 KCNH2;201 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 0 -Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes. 6565573 COL4A5;133559 COL4A4;20071 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 0 -In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. 6707335 SPG11;41614 UBQLN2;81830 E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 0 -@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNQ1;85014 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -2.3. Functional Consequences of the @GENE$-@VARIANT$ and KCNH2-p.C108Y Variants To investigate the functional consequences of KCNQ1-p.R583H and @GENE$-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells. 5578023 KCNQ1;85014 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 0 - Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. 6707335 SPG11;41614 UBQLN2;81830 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941 0 -Many of the @GENE$ mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, @VARIANT$, R165W, F191L, and A197S in Cx26 as well as F193C, @VARIANT$ and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (Cx26, @GENE$, and Cx32) suggested that the EC2 and TM4 domains are important to the function of the Cx31 protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear. 2737700 Cx26;2975 Cx31;7338 M163L;tmVar:p|SUB|M|163|L;HGVS:p.M163L;VariantGroup:7;CorrespondingGene:2706;RS#:80338949 S198F;tmVar:p|SUB|S|198|F;HGVS:p.S198F;VariantGroup:14;CorrespondingGene:2705 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -The brother who is homozygous (II.4) for the @GENE$/TACI @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. 5671988 TNFRSF13B;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -The @GENE$ @VARIANT$ (p.His596Arg) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -18 , 19 This gene codes for several isoforms, including the ubiquitously expressed p200 @GENE$, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by OGG1. 20 The identified CUX1 (NM_001202543: @VARIANT$, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 7689793 CUX1;22551 TRIP6;37757 c.1438A > G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849 c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 DVL3;20928 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 0 -Exome analysis of the proband's DNA identified a heterozygous C to T transition at Exon 18 of @GENE$ (NG_016168.2:g.139841C>T; NM_002336.3:@VARIANT$) (Figure 1A). This sequence variant changes a glutamine codon (CAG) to a translation termination codon (TAG) at position 1252 (NP_002327.2:p.Gln1252*) and will likely subject the altered transcript to nonsense mediated decay. The mutation is not documented in the Genome Aggregation Database (gnomAD) or the Taiwan BioBank database. In addition, a missense sequence variant in @GENE$ (NG_012179.1:g.6853G>A; NM_025216.3:c.338G>A; NP_079492.2:@VARIANT$) was also identified (Figure S1A). 8621929 LRP6;1747 WNT10A;22525 c.3754C>T;tmVar:c|SUB|C|3754|T;HGVS:c.3754C>T;VariantGroup:4;CorrespondingGene:4040 p.Arg113His;tmVar:p|SUB|R|113|H;HGVS:p.R113H;VariantGroup:3;CorrespondingGene:80326;RS#:749324327;CA#:2113880 1 -Proband 17 inherited @GENE$ @VARIANT$ and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out. 8152424 CHD7;19067 CCDC88C;18903 p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636 p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125 0 -For example, two variants in proband P15, p. Ala103Val in @GENE$ and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. 8152424 PROKR2;16368 FGFR1;69065 p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 SOX10;5055 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first @GENE$ transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, @GENE$ variants @VARIANT$ (synonymous) and c.*38T>G (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-AS1 genes. 6338360 PITX2;55454 FOXC2;21091 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 p.S36S;tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 SNAI2;31127 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -@GENE$ @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction. LIMITATIONS Our study was performed only in the statistical field on @GENE$ @VARIANT$ and SCN5A p.R1865H by WES and predisposing genes analyses. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 SCRIB;44228 PTK7;43672 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -We identified four genetic variants (@GENE$-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$) in an LQTS family. 5578023 KCNQ1;85014 KCNH2;201 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 - @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and @GENE$ mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 @VARIANT$ mutations. 7067772 EPHA2;20929 SLC26A4;20132 p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403 0 -The c.1787A>G (@VARIANT$) mutation of @GENE$ has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The c.317G>C (@VARIANT$) variant of @GENE$, a rare single nucleotide polymorphism (SNP, rs544478083), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), MBD5 (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, p.Arg896Trp), all of which were inherited. 6371743 GAMT;32089 NRXN1;21005 p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 KAL1;55445 NELF;10648 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (@VARIANT$ and rs882709 in @GENE$, and @VARIANT$ in @GENE$). 4293318 SETX;41003 EWSR1;136069 rs3739927;tmVar:rs3739927;VariantGroup:65;CorrespondingGene:23064;RS#:3739927 rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143 0 -One patient had a novel de novo variant of @GENE$ (c.1524delA, @VARIANT$) and a hot spot variant of @GENE$ (@VARIANT$, p. Trp178Ser) simultaneously. 8796337 KAl1;55445 PROKR2;16368 p. Ser509fs;tmVar:p|FS|S|509||;HGVS:p.S509fsX;VariantGroup:19;CorrespondingGene:3730 c.533G > C;tmVar:c|SUB|G|533|C;HGVS:c.533G>C;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917 1 -Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees. 6081235 GNA14;68386 MYOD1;7857 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 HS1BP3;10980 VPS13C;41188 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: @VARIANT$; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a). The @GENE$ variant [NM_033056: c.3101G > A; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892). 6053831 USH1G;56113 PCDH15;23401 55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217 c.3101G > A;tmVar:c|SUB|G|3101|A;HGVS:c.3101G>A;VariantGroup:2;CorrespondingGene:124590 0 -Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). 5765430 NR5A1;3638 ZFPM2;8008 p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681 c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963 1 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -He had no mutations in CHD7, FGF8, FGFR1, @GENE$, PROKR2, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) @GENE$ variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352). Since @VARIANT$ was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease. 3888818 PROK2;9268 NELF;10648 Thr478;tmVar:p|Allele|T|478;VariantGroup:0;CorrespondingGene:26012;RS#:121918340 p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218 0 -(D) @GENE$ missense mutation. Lam, Laminin G domain; GAIN, GPCR-autoproteolysis inducing (GAIN) domain; 7tm_2, 7 transmembrane receptors. (E) @GENE$ missense mutation. MTHFR, methylenetetrahydrofolate reductase One individual (283F06) was heterozygous for a novel missense variant in the catalytic N-terminal domain of the methylenetetrahydrofolate reductase (MTHFR) gene (c.601C>T; @VARIANT$) (Figure 2D), which was predicted to be damaging by all 6 mutation predictors tested (Table 1). This individual was also heterozygous for the common MTHFR @VARIANT$ variant, and also carries a rare glycine decarboxylase (GLDC) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. 5887939 CELSR1;7665 MTHFR;4349 p.His201Tyr;tmVar:p|SUB|H|201|Y;HGVS:p.H201Y;VariantGroup:15;CorrespondingGene:2068;RS#:756740686 c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990 0 -We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). 2737700 GJB3;7338 GJB2;2975 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L @GENE$ proteins, respectively (figure 2D, E). 7279190 TTC26;11786 FLNB;37480 p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989 p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246 1 -Moreover, the MAF of @GENE$-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and KCNE1-p.G38S were much larger (0.187 and 0.352, respectively). @GENE$-p.@VARIANT$ is not reported in the ExAC database. 5578023 KCNQ1;85014 KCNH2;201 R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 0 -The genotypes of @GENE$ (NM_001257180.2: @VARIANT$, p.His596Arg) and PDGFRB (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding SLC20A2, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Pedigree and sequence chromatograms of the patient with the @VARIANT$ in MYO7A and c.158-1G>A in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, @VARIANT$ in intron 3 of PCDH15, was derived from the proband and his father. 3949687 PCDH15;23401 MYO7A;219 p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 0 - Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus. 4998745 GJB3;7338 GJB6;4936 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$). 3888818 NELF;10648 TACR3;824 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -The c.229C>T (@VARIANT$) variant in @GENE$ and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2. Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking S100A3, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder. 6637284 S100A3;2223 S100A13;7523 p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 -(A) In addition to c.235delC in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). 4998745 MITF;4892 GJB2;2975 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, @GENE$ @VARIANT$ (p.Leu10Met) and @GENE$ @VARIANT$ (p.Arg248Cys). 7463850 GRIN2A;645 PLXNB2;66630 c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903 c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520 0 -Mutagenesis Sequence variants @GENE$-@VARIANT$ (p.C108Y) and @GENE$-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. 5578023 KCNH2;201 KCNQ1;85014 c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 1 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; @VARIANT$ of @GENE$). 3888818 NELF;10648 TACR3;824 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 1 -Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 TEK;397 CYP1B1;68035 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 0 -The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the @GENE$/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin. 5671988 TNFRSF13B;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$). 2737700 Cx31;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 GJB2;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in @GENE$, rs143224912 in SETDB1 and @VARIANT$ in @GENE$, and one novel variant in S100A13, were identified. 6637284 ISG20L2;12814 S100A3;2223 rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737 rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706 0 -Among these four mutations, while the c.503T>G variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS. 8621929 LRP6;1747 WNT10A;22525 rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216 0 -Moreover, the existence of incomplete penetrance, variable expressivity and of a relatively high proportion (close to 20%) of PCG patients with rare heterozygous @GENE$ variants also suggest non-Mendelian PCG transmission in some cases. In these patients, disease outcome might depend on modifier factors (genetic, stochastic and/or environmental), as will be discussed later. Functional impact of the rare variants The two missense FOXC2 variants (p.(H395N) and (p.(C498R)) and one of the PITX2 amino acid substitutions (p.(P179T)) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation. The functional impact of the second PITX2 amino acid substitution, p.(A188T), could not be functionally evaluated due to DNA cloning difficulties. In fact, the two FOXC2 amino acid changes were found to be hypomorphic whereas the @GENE$ amino acid substitution (@VARIANT$) behaved experimentally as a hypermorphic variant. Additional structural and functional analysis indicated that @VARIANT$ alters polypeptide chain conformation and decreases protein stability, which can explain the associated reduced transactivation. 6338360 CYP1B1;68035 PITX2;55454 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303 0 -On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b). 7067772 EPHA2;20929 SLC26A4;20132 p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772 c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -These data also indicate that an alternate pathway is used for quality control of pro-@GENE$ when @GENE$ alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. 4853519 COL1A1;73874 MAN1B1;5230 1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3). 3888818 KAL1;55445 NELF;10648 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the @GENE$ (@GENE$) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the HNF1A gene. 8306687 glucokinase;55440 CGK;55964 c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645 p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336 0 -M2, @GENE$: @VARIANT$. M3, CYP1B1: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases. 6338360 CYP1B1;68035 PITX2;55454 p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -We report digenic variants in @GENE$ and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 SCRIB;44228 CELSR1;7665 c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) 0 -Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; @VARIANT$), and @GENE$ (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. 4470809 OPTN;11085 TBK1;22742 p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 1 -Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 FGFR1;69065 p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. 3125325 USH1G;56113 USH2A;66151 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. 6707335 SPG11;41614 UBQLN2;81830 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. 3842385 EDA;1896 WNT10A;22525 G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -II: 1 carried the digenic heterozygous mutations of KCNH2 @VARIANT$ and SCN5A @VARIANT$. I: 1 and II: 2 were heterozygous for @GENE$ p.R1865H. Except II: 1, other family members did not carry @GENE$ mutation. 8739608 SCN5A;22738 KCNH2;201 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. 3842385 EDA;1896 WNT10A;22525 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. 6707335 ALS2;23264 MATR3;7830 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). 8172206 SLC20A2;68531 PDGFRB;1960 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 0 -This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same PROKR2 heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in @GENE$, @VARIANT$;p.A604T (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. @GENE$ and PROKR2 are both expressed in the hypothalamus and pituitary, and reduced expression or activity of PROKR2 is implicated in both Kallmann syndrome and PSIS, perhaps because of the important role this signaling pathway plays in endocrine angiogenesis and neuronal migration in this region of the central nervous system. 5505202 FGFR1;69065 Prokineticin 2;9268 p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418 c.1810G>A;tmVar:c|SUB|G|1810|A;HGVS:c.1810G>A;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644 0 -The @GENE$ @VARIANT$ (p.His596Arg) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ @VARIANT$ (p.Arg106Pro) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Coimmunoprecipitation analysis indicated an interaction between wild-type @GENE$ and wild-type FLNB, which did not exist between @VARIANT$ @GENE$ and @VARIANT$ OFD1 (figure 3D). 7279190 OFD1;2677 FLNB;37480 p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226 p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481 0 -We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. 2737700 GJB2;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Mutations of the residues could affect the function of the human @GENE$ protein. In the case of R171C mutations, the substitution of Cys, a hydroxylic amino acid with a side chain shorter than Arg, might eliminate the electrostatic interaction of R171 with adjacent residues. The mutation G213S is expected to abolish the hydrophobic interaction of G213 with adjacent residues. Sequences of orthologs and predicted 2D structure of human WNT10A protein. (A) The alignment of orthologs of the human WNT10A protein. The R171 and @VARIANT$ residues are represented by arrowheads. (B) The predicted 2D structure of human WNT10A protein. The R171 and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When @VARIANT$ mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of @GENE$ with its receptors. 3842385 WNT10A;22525 EDA;1896 G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216 G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (@VARIANT$) exhibit perturbed interaction. 5953556 TEK;397 CYP1B1;68035 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 1 - Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). 8621929 LRP6;1747 WNT10A;22525 c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 1 -For Case 1, a novel missense VUS (variant of unknown significance) variant (c.361C>T; @VARIANT$) in the @GENE$ gene was identified in the patient and his father. A rare variant in @GENE$, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS. 7696449 STAR;297 AMH;68060 p.Arg121Trp;tmVar:p|SUB|R|121|W;HGVS:p.R121W;VariantGroup:7;CorrespondingGene:6770;RS#:34908868;CA#:4715265 p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862 0 -Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (@VARIANT$). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2). 3125325 USH2A;66151 MYO7A;219 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) 0 -The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/@GENE$ @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family. 5671988 TCF3;2408 TACI;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 1 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), MBD5 (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited. 6371743 GAMT;32089 NRXN1;21005 p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of @GENE$ (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) . 5587079 DUOX1 and -2;53905;50506 DUOX1;68136 p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 0 -Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. 5868303 SQSTM1;31202 TIA1;20692 c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired) c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB @VARIANT$). 5887939 DVL3;20928 CELSR1;7665 c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -(E) The @GENE$ mutation c.466C>T and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and @VARIANT$ in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained. 3842385 EDA;1896 WNT10A;22525 c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 - A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 1 -In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/@GENE$, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k). 2737700 GJB3;7338 GJB2;2975 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father). 3975370 IL10RA;1196 NOD2;11156 R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 1 -Four genes (including @GENE$, ZFHX3, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies. 5725008 AGXT2;12887 TCF4;2407 p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 -In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. 6707335 SPG11;41614 UBQLN2;81830 E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 0 -Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic @GENE$ p.T511M and SLC26A4 @VARIANT$ mutations. 7067772 pendrin;20132 EPHA2;20929 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). 2737700 Cx31;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -(A) Segregation of the @GENE$-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members. 5578023 KCNQ1;85014 KCNH2;201 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. 6081235 TOR2A;25260 ATP2A3;69131 p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346 p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 0 -These results suggest an important role of @GENE$ as an inducer of @GENE$ endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. 7067772 ephrin-B2;3019 EphA2;20929 A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for CDH23 , 11%-15% for PCDH15 , and for @GENE$ in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor. 3125325 USH1C;77476 USH2A;66151 c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$). 6567512 BBS1;11641 BBS7;12395 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in exon 3 of @GENE$ were detected. 3842385 EDA;1896 WNT10A;22525 p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 1 -Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. 6637284 S100A3;2223 S100A13;7523 rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 1 -On the basis of the data collected in this study, we may speculate that the presence of @GENE$-@VARIANT$, together with three KCNE1-p.G38S alleles, could lead to an increased risk of developing cardiac arrhythmias due to the prolongation of the QT interval. Moreover, the overt LQTS phenotype in our family could be caused by the co-expression, in cardiac cells, of KCNH2-p.C108Y and @GENE$-@VARIANT$. The condition of digenic heterozygosity has been associated with a more severe phenotype, a higher risk of life-threatening events, and a reduced efficacy of beta blocking therapy. 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature. 3975370 NOD2;11156 IL10RA;1196 2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 0 -Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation @VARIANT$ in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes. 6565573 COL4A5;133559 COL4A3;68033 c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174 Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 0 -In our study, @VARIANT$(p. Arg631*) and @VARIANT$(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and c.1524del A(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of @GENE$ gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function. Prokineticin-2 (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed @GENE$/PROKR2 variants, which was significantly higher than the 9% in the Caucasian population. 8796337 KAl1;55445 PROK2;9268 c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223 c.1267C > T;tmVar:c|SUB|C|1267|T;HGVS:c.1267C>T;VariantGroup:7;CorrespondingGene:3730 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 - A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A). 5887939 SCRIB;44228 FAT4;14377 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776 0 -25 The @GENE$ (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25 The contribution of the genetic variants, other than MSH6 and @GENE$, to cancer risk cannot be completely excluded. 7689793 RYR3;68151 MUTYH;8156 c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988 c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 0 -The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 @VARIANT$ and @GENE$/TACI C104R mutations are shown. 5671988 TCF3;2408 TNFRSF13B;49320 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug KCNE1-WT or 1 mug @GENE$-@VARIANT$ + 1 mug KCNE1-WT) or 3 mug (1.5 mug KCNH2-WT + 1.5 mug @GENE$-@VARIANT$ or 1.5 mug KCNH2-WT + 1.5 mug empty vector) plasmid per dish were used. 5578023 KCNQ1;85014 KCNH2;201 c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). 2737700 Cx31;7338 GJB2;2975 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 1 -No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the @GENE$ protein, which affected a secondary CYP1B1-binding site. 5953556 CYP1B1;68035 TEK;397 A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327 0 -33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (@VARIANT$) and PKHD1: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3). 8256360 PKD1;250 PKHD1;16336 p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402 p.R559W;tmVar:p|SUB|R|559|W;HGVS:p.R559W;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488 1 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6. 6610752 LQT6;71688 LQT2;201 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 0 -Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), RYR1 (rs143445685), @GENE$ (@VARIANT$), and DES (rs144901249) genes. 6180278 COL6A3;37917 CAPN3;52 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 0 -Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for @GENE$, @GENE$, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with RIPK4. 6726737 EVC;10949 FGF10;3284 p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322 c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269 0 -(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. 4998745 GJB2;2975 GJB6;4936 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with @GENE$ @VARIANT$ and SETX p.T14I). 4293318 ANG;74385 SETX;41003 p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953 p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108 0 -Similarly, the @GENE$-mutated case P05 in our study carried additional variants in @GENE$ (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. 8152424 CCDC88C;18903 DCC netrin 1 receptor;21081 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 TEK;397 CYP1B1;68035 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 1 -GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins @VARIANT$ and I148T exhibited diminished interaction with wild-type GFP-@GENE$. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. 5953556 TEK;397 CYP1B1;68035 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(@VARIANT$) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) PKD2 variant. 7224062 PKD2;20104 PKD1;250 Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716 Ser872Gly;tmVar:p|SUB|S|872|G;HGVS:p.S872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061 0 -The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of PROKR2 were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD. 8446458 DUSP6;55621 SEMA7A;2678 c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709 0 -"The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein. However, the two rare FUS variants (Y25C and @VARIANT$) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein. Although the majority of FUS mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging. In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD)." 6707335 ubiquilin-2;81830 FUS;2521 P106L;tmVar:p|SUB|P|106|L;HGVS:p.P106L;VariantGroup:7;CorrespondingGene:2521;RS#:374191107;CA#:8023567 K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 - In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. @GENE$ mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (p.Gly226Ser) was identified in @GENE$ (table 1). 6161649 N-cadherin;20424 IL17RD;9717 c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730 c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588 0 -To investigate the effects of one candidate variant on mutant @GENE$ function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father. 5505202 WDR11;41229 PROKR2;16368 c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601 c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 0 -Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. 6707335 GRN;1577 SQSTM1;31202 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 0 -WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus. 5505202 PROKR2;16368 EMX1;55799 c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601 c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 0 -DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 TYRO3;4585 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -(B) The predicted 2D structure of human @GENE$ protein. The @VARIANT$ and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The @VARIANT$ and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the EDA trimer. (B) The side view of the EDA trimer. Discussion This is the first study to show that simultaneous WNT10A and @GENE$ mutations could lead to tooth agenesis in the Chinese population. 3842385 WNT10A;22525 EDA;1896 R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555 G257;tmVar:c|Allele|G|257;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 KAL1;55445 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$). 6567512 BBS1;11641 BBS2;12122 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 0 -In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/@GENE$, while the mother is heterozygous for the @GENE$/@VARIANT$ (Fig. 1k). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204 0 -CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in @GENE$ were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant @VARIANT$ of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. @GENE$ seems to act similarly as CCDC88C through a digenic/oligogenic model to contribute to IHH. 8152424 CCDC88C;18903 CDON;22996 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125 0 -In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). 2737700 GJB6;4936 GJB2;2975 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -We propose that cysteine to arginine change in position 238 of @GENE$ lacks activity to bind DNA reducing the transactivation of AMH critically. By contrast, variants @VARIANT$ and p@VARIANT$ found in cases 2 and 3 did not affect @GENE$ promoter activity. 5893726 GATA4;1551 CYP17;73875 p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748 Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038 0 -Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). 5953556 TEK;397 CYP1B1;68035 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -In the subject III.1, the variant, carried in the heterozygous status, is the c.868 G > T; @VARIANT$, in the @GENE$ (@GENE$) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the HNF1A gene. 8306687 glucokinase;55440 CGK;55964 p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645 p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336 0 -@GENE$ mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. 5868303 SQSTM1;31202 TIA1;20692 c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired) p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons. 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 - Cloning and site directed mutagenesis of @GENE$ and @GENE$ variants The FOXC2 variants p.(C498R) (@VARIANT$) and @VARIANT$ were directly amplified and cloned from the genomic DNA of carriers using the following primers, which incorporated the EcoRI or BamHI restriction sites at the 5' end (indicated in bold): FOXC2-Up-EcoRI, 5'-GGGAATTCCGCGCTCTCTCGCTCTCAGG-3' and FOXC2-Dw-BamHI, 5'-GGGGATCCCCGTATTTCGTGCAGTCGTAGG-3'. 6338360 FOXC2;21091 PITX2;55454 rs61753346;tmVar:rs61753346;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346 p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in @GENE$ and @GENE$ contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death. 6371743 NRXN1;21005 NRXN2;86984 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 1 -In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (@GENE$ c.8282C>T and SCRIB @VARIANT$). 5887939 PRICKLE4;22752 CELSR1;7665 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -The genotypes of SLC20A2 (NM_001257180.2: c.1787A>G, @VARIANT$) and @GENE$ (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding PDGFRB, G/C = heterozygous mutation carrier, and G/G = wild type. 8172206 PDGFRB;1960 SLC20A2;68531 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I). 4293318 TARDBP;7221 FUS;2521 p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). 6161649 ENG;92 BMP;55955 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778 0 -A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant c.1777C > G (@VARIANT$) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. 7463850 SLC9A6;55971 EHMT1;11698 p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502 p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465 0 -The variant pair CCDC141 (@VARIANT$)-PROKR2 (@VARIANT$) was classified by ORVAL as true digenic. The contribution of the three missense variants in @GENE$ and @GENE$ genes, which were homozygous in the index case and heterozygous in the asymptomatic cases (Table 2), to the total number of pathogenic digenic combinations did not differ among the three family members (Figure 4). 8446458 IL17RD;9717 PCSK1;379 c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885 c.868C > T;tmVar:c|SUB|C|868|T;HGVS:c.868C>T;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257 0 -Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. 7067772 pendrin;20132 EPHA2;20929 L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -20 The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and @GENE$ (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 7689793 EBNA1BP2;4969 CAPN9;38208 p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849 p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675 0 -One patient (f93-80) had a novel @GENE$ missense variant (@VARIANT$) with a rare @GENE$ missense variant (@VARIANT$). 5887939 PTK7;43672 CELSR2;1078 c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 1 -Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in @GENE$. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. 3125325 USH2A;66151 USH1G;56113 p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 0 -Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 @VARIANT$ gene. 5671988 TCF3;2408 TACI;49320 c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls. 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas @GENE$ @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant. 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. 6161649 SCUBE2;36383 VEGFR2;55639 p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, @VARIANT$ in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. 3125325 MYO7A;219 USH2A;66151 c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A. 3125325 MYO7A;219 USH1C;77476 c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 SNAI2;31127 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 TRPV4;11003 SPTBN4;11879 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -C2orf74 gene might interact with @GENE$ gene product and give rise to the spectrum of phenotype varying from severe phenotype with complete penetrance to partial features. Conclusion In this study, we analysed a large family segregating Waardenburg syndrome type 2 to identify the underlying genetic defects. Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the MITF gene and a rare heterozygous, missense damaging variant (c.101T>G; @VARIANT$) in the @GENE$ was identified. 7877624 MITF;4892 C2orf74;49849 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 0 -"Nevertheless, when it occurs with a defect in @GENE$, which functions in the same pathway, a combination of deficiencies results in a severe disease phenotype. This phenomenon of ""synthetic lethality"" has long been described in genetics and thought to be implicated in the molecular pathogenesis of digenic inheritance in genetic disorders. In this study, we also showed that a second @GENE$ variant in trans might potentially modify the expressivity of a primary ""driver"" mutation. The proband of Family 3 was a compound heterozygote of p.(@VARIANT$) and p.(@VARIANT$) mutations and had fourteen missing teeth, while his father, who carried the p.(Ala754Pro) mutation, exhibited only two." 8621929 WNT10A;22525 LRP6;1747 Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 0 -@GENE$-@VARIANT$ is an unknown variant. The @GENE$-@VARIANT$ variant is currently annotated as a mutation in the Human Gene Mutation Database (HGMD) database, having been identified in other LQTS subjects. 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). 5887939 DVL3;20928 SCRIB;44228 c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. 3125325 MYO7A;219 CDH23;11142 p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 0 -The proband's son (III.1) has inherited the @GENE$ @VARIANT$ mutation, but not the @GENE$/TACI @VARIANT$ mutation. 5671988 TCF3;2408 TNFRSF13B;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 - Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). 8621929 LRP6;1747 WNT10A;22525 c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 1 -In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). 2737700 GJB2;2975 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -The mutations of KCNH2 @VARIANT$ and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous SCN5A p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a). Except II: 1, other family members without cardiac event or cardiac disease did not carry KCNH2 mutation. Moreover, the conservation analyses demonstrated that the mutant sites of amino acid sequences of @GENE$ and @GENE$ protein were highly conserved (Figure 2). 8739608 SCN5A;22738 KCNH2;201 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -These phenomenon indicate that the mutated SCAP-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated @GENE$ coding protein. @GENE$-c.1103C>T (@VARIANT$) variant impaired the catabolism of ADMA in EA. 5725008 SCAP;8160 AGXT2;12887 p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 - CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of @GENE$ protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction. LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and SCN5A p.R1865H by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 p.307_308del and SCN5A @VARIANT$ increases the risk of the early-onset LQTS and sinoatrial node dysfunction. 8739608 KCNH2;201 Nav1.5;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB6;4936 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -The most common mutation was p.R1110Q (DUOX2: @VARIANT$), which was found in 5 patients, accounting for 11% of all the cases. Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A). A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, DUOXA2 and TPO). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes. 7248516 SLC26A4;20132 TPO;461 c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;VariantGroup:12;CorrespondingGene:50506;RS#:368488511;CA#:7537915 p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991 0 -The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087 R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852 0 -a, b Immunoprecipitation of @GENE$ with mutated pendrin. myc-pendrin A372V, @VARIANT$, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by @GENE$ stimulation. 7067772 EphA2;20929 ephrin-B2;3019 L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 CYP1B1;68035 TEK;397 p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 0 - Missense variants in the @GENE$ gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. 6707335 NEFH;40755 GRN;1577 P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 0 -Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS. 8621929 LRP6;1747 WNT10A;22525 rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). 8172206 SLC20A2;68531 PDGFRB;1960 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 0 -We report digenic variants in @GENE$ and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 SCRIB;44228 PTK7;43672 c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 FGFR1;69065 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730 0 -In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and PKD2 (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly). 7224062 PKD1;250 PKD2;20104 Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907 Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716 0 - Finally, a subject with the heterozygous p.R143W mutation in GJB2 (SH60-136) carried a p.D771N variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES. However, neither @VARIANT$ in GJB2 nor p.D771N in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3). As a result, @GENE$ was excluded for SH60-136. Pedigree and audiograms of SH60 and segregation of variations of GJB2 and WFS1 in this family: two subjects with SNHL, SH60-138 and SH60-142, showed a discrepancy in the GJB2 genotype. Two unaffected subjects, SH60-137 and SH60-139, also carried @VARIANT$ in WFS1. 4998745 WFS1;4380 DFNB1;2975 p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234 p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681 0 -On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, @GENE$-@VARIANT$ and @GENE$-@VARIANT$, using the whole-cell patch clamp technique. 5578023 KCNQ1;85014 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 1 -One IHH patient had compound heterozygous @GENE$ mutations (@VARIANT$ and c.629-23G>C); and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$). 3888818 NELF;10648 TACR3;824 c.629-21C>G;tmVar:c|SUB|C|629-21|G;HGVS:c.629-21C>G;VariantGroup:4;CorrespondingGene:26012;RS#:768001142;CA#:5370502 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Notably, not all @GENE$-Q1916R carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by SCN5A-@VARIANT$ variant and sex. As shown in Table 3, all male individuals carrying the CACNA1C-Q1916R mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant @GENE$-R1193Q showed the ERS phenotypes. The female CACNA1C-Q1916R mutation carriers with SCN5A-R1193Q variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the CACNA1C-@VARIANT$ mutation (IV-4) showed the ER ECG pattern. 5426766 CACNA1C;55484 SCN5A;22738 R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 0 - Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (@VARIANT$), and @GENE$, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The TIA1 variant and @GENE$ variants have been reported in multiple databases. 5868303 TIA1;20692 SQSTM1;31202 p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 0 -However, SCN5A @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure. RNA secondary structural prediction. (a, b) Compared with wild-type @GENE$, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of @GENE$ p.R1865H mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability. 8739608 KCNH2;201 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -We observed that recombinant TEK and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of @GENE$ (p.E103D)::CYP1B1 (@VARIANT$), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction. 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Most had C9orf72 repeat expansion combined with another mutation (e.g. VCP @VARIANT$ or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, P372R in @GENE$ and @VARIANT$ in TARDBP. 5445258 TARDBP;7221 ALS2;23264 R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983 A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343 0 -Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. 5953556 TEK;397 CYP1B1;68035 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:@VARIANT$; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to @GENE$ in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (@GENE$). 4470809 OPTN;11085 FUS;2521 c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281 c.2086G>A;tmVar:c|SUB|G|2086|A;HGVS:c.2086G>A;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889 0 -Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the @GENE$ mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus lead to a reduction of structural stability. However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). 8739608 KCNH2;201 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. Based on the seemingly normal reproductive phenotype of Sema3a +/- heterozygous mice, we suggest that the monoallelic mutations in SEMA3A are not sufficient to induce the abnormal phenotype in the patients, but contribute to the pathogenesis of KS through synergistic effects with mutant alleles of other disease-associated genes. Accordingly, the other KS patients who carry monoallelic mutations in @GENE$ are also expected to carry at least one pathogenic mutation in another gene (see footnote). 3426548 KAL1;55445 SEMA3A;31358 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071 0 -At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/@GENE$ signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (@VARIANT$) was identified in @GENE$ (table 1). 6161649 Akt;3785 IL17RD;9717 c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588 p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$). 6567512 BBS1;11641 BBS6;10318 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 - Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -"The results of our study and the @GENE$ study consistently suggested that the rate of oligogenic inheritance of IHH genes varies and maintains at high levels. According to our data, eight patients had at least two IHH gene variants. Two patients carried three variants and one patient even carried four variants. Our data supported ""additive effect"" and ""cumulative mutation burden"" that were proposed in studies related to IHH. For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant." 8152424 PLXNA1;56426 DCAF17;65979 p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$). 6610752 LQT2;201 LQT6;71688 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 1 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$). 3888818 KAL1;55445 TACR3;824 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Phenotype penetrance CACNA1C-@VARIANT$ +/-SCN5A-R1193Q +/- CACNA1C-Q1916R +/-SCN5A-@VARIANT$ -/- CACNA1C-Q1916R -/-@GENE$-R1193Q -/- Male 100% (4/4 cases) 100% (1/1 case) 0 (0/1 cases) II-4, III-1, III-5, IV-3 III-7 III-3 Female 0 (0/4 cases) 100% (1/1 case) 0 (0/4case) II-3, II-6, III-4, IV-1 IV-4 II-5, III-2, III-6, III-8 Dysfunctional electrophysiology and drug intervention in mutated CaV1.2alpha1C To determine the molecular consequences of the CACNA1C-Q1916R mutation, we transfected @GENE$ with the other 2 subunits (CACNB2b and CACNA2D1) forming the LTCC into HEK293T cells and performed whole cell patch-clamp experiments. 5426766 SCN5A;22738 CACNA1C;55484 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 0 -In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 - A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 - Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. 4998745 GJB3;7338 MITF;4892 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. 6081235 CACNA1A;56383 REEP4;11888 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas @GENE$ p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. 8739608 KCNH2;201 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 KAL1;55445 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 1 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6. 6610752 LQT6;71688 LQT2;201 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 0 -33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (p.R559W) and PKHD1: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3). 8256360 PKD1;250 PKHD1;16336 p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402 c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDNRB;89 PAX3;22494 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$). 5887939 FZD6;2617 FAT4;14377 c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818 c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the @GENE$ (CGK) gene; the III.2 subject carried the @VARIANT$; p.Pro291Arg, in the @GENE$ gene. 8306687 glucokinase;55440 HNF1A;459 c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645 c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336 0 -RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). 2737700 Cx26;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 @VARIANT$ and @GENE$ @VARIANT$). 5887939 DVL3;20928 SCRIB;44228 c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a). 2737700 GJB2;2975 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Determination of the evolutionary sequence conservation of @GENE$ in different species revealed that the amino acid corresponding to V255 is fully conserved (Fig. 3e). In contrast, the serine at position 300 was less well conserved, several species depicting proline in this position, although the surrounding amino acid sequences were highly conserved. For example, the sequence homology between the human and mouse 23-amino acid sequence segment surrounding the S300 was 95.7 percent (Fig. 3f). Sequencing of the VKORC1 gene did not disclose any pathogenic mutations. Genotype/phenotype correlations A correlation of the clinical findings with the genotypes revealed that the proband and her sister were compound heterozygotes for the two GGCX missense mutations, potentially explaining their hematologic findings. In contrast, the proband's father, brother, her mother, and the mother's twin sister were heterozygous for one of the GGCX mutations only, designating them as carriers without clinical hematologic findings (Fig. 1g). The latter individuals were also carriers of the @GENE$ nonsense mutation p.R1141X. Specifically, the mother and her twin sister were heterozygous for the GGCX missense mutation @VARIANT$ and the ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. 2900916 GGCX;639 ABCC6;55559 p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 0 -Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 TYRO3;4585 SNAI3;8500 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 PRICKLE4;22752 FAT4;14377 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818 0 -RESULTS Mutations at the gap junction proteins Cx26 and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). 2737700 Cx31;7338 GJB6;4936 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Except for the @GENE$ @VARIANT$ variant, all of the variants were classified as uncertain significance of pathogenicity, implying that functional studies should be conducted in the future to provide additional evidence for the pathogenicity of those novel variants in IHH. A total of 24 rare variants were identified in 77.8% (14/18) of the IHH-affected cases in this study. All of those variants were heterozygous, and most were missense and dispersedly distributed in cases, indicating strong complexity and heterogeneity of IHH. PROKR2 had the highest variant frequency (4/18, 22.2%) in our study. Although @GENE$ variant @VARIANT$ has a relatively high allele population frequency (0.002-0.003) in East Asians, It was proven in previous studies to be functional damaging using in vitro functional assays and was enriched in our IHH cohort. 8152424 FGFR1;69065 PROKR2;16368 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:0;CorrespondingGene:128674;RS#:201835496;CA#:270917 0 -"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and @VARIANT$ variants are known variants reported by other study groups. 6707335 GRN;1577 SQSTM1;31202 T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087 R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852 0 -Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (@VARIANT$)::CYP1B1 (p.A115P), TEK (p.Q214P)::@GENE$ (p.E229K), and @GENE$ (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. 5953556 CYP1B1;68035 TEK;397 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -"Circles: females; squares: males; white symbols: not included in the study; white symbols with genotype: unaffected; black symbols: pulmonary fibrosis affected; +: wild-type ""C"" allele of @GENE$/wild-type sequence of S100A13; -: mutant ""T"" allele of S100A3 (@VARIANT$)/4 bp deletion of @GENE$ (@VARIANT$)." 6637284 S100A3;2223 S100A13;7523 c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284 0 -Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. 5953556 TEK;397 CYP1B1;68035 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 1 -The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the @GENE$ gene (p.S300F) yet did not display any cutaneous findings are not clear. Specifically, while both GGCX mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the @VARIANT$ mutation was more pronounced than that of p.V255M. 2900916 ABCC6;55559 GGCX;639 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 Cx31;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (@GENE$) and connexin 31 (@GENE$) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 Cx26;2975 Cx31;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 1 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). 5953556 CYP1B1;68035 TEK;397 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 1 - By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). 4998745 GJB2;2975 GJB3;7338 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 1 -Direct sequence analysis showing the @VARIANT$ mutation (b and g) and wild type (WT) allele (c and h) of GJB2. Direct sequence analysis showing the 299-300delAT mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the @VARIANT$ (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3. Expression of @GENE$ and @GENE$ in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and Cx31 (b). 2737700 Cx31;7338 Cx26;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited. 6371743 MBD5;81861 NRXN1;21005 p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 CACNA1A;56383 DNAH17;72102 c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3). 3888818 KAL1;55445 TACR3;824 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 0 -SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/@GENE$ binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (p.Cys531Tyr) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking @GENE$ activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo. In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. 6161649 VEGFR2;55639 SMAD1;21196 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730 0 -In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 Cx26;2975 GJB6;4936 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 SOX10;5055 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. 5953556 CYP1B1;68035 TEK;397 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN1;21005 NRXN2;86984 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 KAL1;55445 FGFR1;69065 p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 TYRO3;4585 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -(a) Digenic inheritance of TNFRSF13B (c.310T>C, @VARIANT$ TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and @GENE$/TACI C104R mutations. 5671988 TCF3;2408 TNFRSF13B;49320 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, @GENE$ and TPO). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 @GENE$ variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and @VARIANT$ were novel. 7248516 DUOXA2;57037 TSHR;315 p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885 p.K618;tmVar:p|Allele|K|618;VariantGroup:4;CorrespondingGene:7253 0 -These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (@VARIANT$; p.E2135fsX31), and six missense mutations, four of which (p.R1189W, p.R1379P, p.D2639G, and @VARIANT$) had not been previously reported. 3125325 harmonin;77476 CDH23;11142 c.6404_6405delAG;tmVar:c|DEL|6404_6405|AG;HGVS:c.6404_6405delAG;VariantGroup:207;CorrespondingGene:65217 p.R3043W;tmVar:p|SUB|R|3043|W;HGVS:p.R3043W;VariantGroup:141;CorrespondingGene:64072;RS#:375907609;CA#:5546888 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 SNAI3;8500 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and @GENE$ (c.9921T>G). 3125325 MYO7A;219 USH2A;66151 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 0 -Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, @GENE$ and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2). 3125325 USH1G;56113 MYO7A;219 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 1 -Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. 6637284 S100A3;2223 S100A13;7523 rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706 c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284 1 -The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the @GENE$ gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between DYNC1H1 variants and ALS. Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (H398R and @VARIANT$) were detected in the GBE1 gene. 6707335 MATR3;7830 DYNC1H1;1053 T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778 R166C;tmVar:p|SUB|R|166|C;HGVS:p.R166C;VariantGroup:21;CorrespondingGene:2632;RS#:376546162;CA#:2499951 0 -The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant. 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). 2737700 Cx31;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 TEK;397 CYP1B1;68035 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and @GENE$-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 1 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene. 6707335 ALS2;23264 DYNC1H1;1053 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). 5887939 PRICKLE4;22752 SCRIB;44228 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 - The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). 7067772 pendrin;20132 EphA2;20929 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 0 -Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$). 8152424 FGFR1;69065 CCDC88C;18903 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). 2737700 Cx31;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in @GENE$ play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. 6359299 LAMA4;37604 MYBPC3;215 L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954 R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212 0 - Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326 0 -Somatic overgrowth associated with homozygous mutations in both @GENE$ and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ c.1200G>C (@VARIANT$) and MAN1B1 c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family. 4853519 MAN1B1;5230 SEC23A;4642 p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SOX10;5055 MITF;4892 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea. 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA." 3842385 EDA;1896 WNT10A;22525 termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 SCRIB;44228 PTK7;43672 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 PTK7;43672 SCRIB;44228 c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 1 -Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; p.Gln235*), and @GENE$ (NM_013254.3:@VARIANT$; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. 4470809 OPTN;11085 TBK1;22742 c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 0 -The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, @GENE$, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 DCC;21081 PROKR2;16368 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482 0 -c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the @GENE$ protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts. 6637284 S100A3;2223 S100A13;7523 arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 -Nevertheless, in vitro studies demonstrated that the @GENE$-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, G38S could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the KCNQ1 and KCNH2 channels. Given the complexity of the LQTS-related genetic background in our family, we functionally characterized only KCNH2-p.C108Y and KCNQ1-@VARIANT$. Our data demonstrate that the activity of KCNH2-p.C108Y was significantly lower than that of the wild type. This variant exerts a dominant-negative effect and shifts the voltage-dependence of activation when co-expressed with KCNH2-WT (Figure 4). Moreover, our data support the hypothesis that this variant, although localized in the PAS domain, which influences protein trafficking, can reach the plasma membrane. Therefore, we may speculate that the functional defect of @GENE$-C108Y could be compromised conductance. 5578023 KCNE1;3753 KCNH2;201 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe). 6567512 BBS7;12395 BBS6;10318 c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. 8152424 DMXL2;41022 CDON;22996 p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930 p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125 0 -Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and @GENE$ (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (FUS). CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of @GENE$ (NM_001008211.1:@VARIANT$; p.Gly538Glufs27). 4470809 TBK1;22742 OPTN;11085 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 c.1243-740_1612+1292delins25;tmVar:c|INDEL|1243-740_1612+1292|25;HGVS:c.1243-740_1612+1292delins25;VariantGroup:37;CorrespondingGene:10133 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and R393Q in single patients. 6707335 GRN;1577 SQSTM1;31202 R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049 P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for @GENE$ , 11%-15% for PCDH15 , and for @GENE$ in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor. 3125325 CDH23;11142 USH2A;66151 c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -GFP-@GENE$ R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-@GENE$ G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). 5953556 CYP1B1;68035 TEK;397 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 0 -The p.R341 residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages. Digenic inheritances of GJB2/MITF and GJB2/GJB3 (group II). (A) In addition to c.235delC in @GENE$, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. 4998745 MITF;4892 GJB2;2975 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Representative western blot and bar graph showing expression levels of @GENE$ (A) and @GENE$ (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. 4853519 SEC23A;4642 MAN1B1;5230 M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes. 6565573 COL4A5;133559 COL4A4;20071 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286 0 -Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel NR5A1 Variants To study the impact of the three novel missense variants of NR5A1 on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant @GENE$ expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel NR5A1 variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the @VARIANT$ and Cys30Ser variants when using the reporters for @GENE$ and HSD17B3 (Figure 2B,C). 7696449 NR5A1;3638 CYP11A1;37347 p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935 His24Leu;tmVar:p|SUB|H|24|L;HGVS:p.H24L;VariantGroup:4;CorrespondingGene:6736;RS#:1262320780 0 -Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 SNAI3;8500 TYRO3;4585 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father). 3975370 IL10RA;1196 NOD2;11156 c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322 K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 1 -The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 0 - Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in SQSTM1 (p.Pro392Leu) and a variant in @GENE$ (@VARIANT$). At the time of this report, only a single prior myopathy case with the same genetic variants has been reported, but the clinical and myopathological features were not illustrated. There are also two further cases of MRV having the same TIA1 variant but a different @GENE$ mutation (@VARIANT$), one of whom was previously reported as having a SQSTM1-MRV. 5868303 TIA1;20692 SQSTM1;31202 p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired) 1 -None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (@VARIANT$). 5868303 TIA1;20692 SQSTM1;31202 c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 1 -Sequencing of the proband's sister's and her aunt's @GENE$ gene revealed the presence of eight heterozygous polymorphisms in the exons 7-19. This finding argues against large allelic deletions at the 5' half of the gene which might not be detectable by the mutation detection strategy employed in our study. Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and VKORC1 genes. The results demonstrated the presence of two missense mutations in @GENE$. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). 2900916 ABCC6;55559 GGCX;639 c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442 p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 0 -On the other hand, EphA2 overexpression did not affect localization of @VARIANT$. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both @GENE$ recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. 7067772 EphA2;20929 pendrin;20132 G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B). 3842385 WNT10A;22525 EDA;1896 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). 3125325 CDH23;11142 MYO7A;219 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 0 -We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe). 6567512 BBS2;12122 BBS7;12395 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -Patient 3 was found to harbor a previously reported p.Arg84His variant in @GENE$, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a @VARIANT$ of NR5A1 (Table 3). 5765430 NR5A1;3638 ZFPM2;8008 c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963 single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516 0 -N393D <0.001 @VARIANT$ 0.005(D) 0.109 (B) Muscular dystrophy chr7 150648538 CCA - KCNH2 NM_001204798:exon3:c.921_923del:p.307_308del - - - - Short QT syndrome; long QT syndrome chrX 31854929 T A DMD NM_004011:exon21:c.A3083T:@VARIANT$ - - 0.054(T) 0.999 (D) Cardiomyopathy; muscular dystrophy Note: Chr, chromosome; 1000G, 1000 genomes (2015 version); SNP, single nucleotide polymorphism; B, benign; D, damaging; T, tolerated; -, no report; OMIM, Online Mendelian Inheritance in Man. Conservation analyses at the mutant sites of SCN5A and KCNH2 protein. SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and KCNH2 mutations. @GENE$ p.307_308del and @GENE$ p.R1865H of the proband were validated as positive by Sanger sequencing. 8739608 KCNH2;201 SCN5A;22738 rs147301872;tmVar:rs147301872;VariantGroup:2;CorrespondingGene:3908;RS#:147301872 p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757 0 -In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in @GENE$/TGF-beta signalling. 6161649 ENG;92 BMP;55955 c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022 p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 0 - Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. 6707335 SPG11;41614 ubiquilin-2;81830 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -Two additional variants, @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively. 6072915 RYR1;68069 CACNA1S;37257 p. T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146 p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268 0 -"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys." 3842385 EDA;1896 WNT10A;22525 termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -The proband from Family 1 is consistent with the H1 haplotype based on the presence of homozygous genotypes for @VARIANT$ and rs4797 although this is not definitive because the rs10277 and rs1065154 polymorphisms were not covered. The haplotype of the proband from Family 2 could not be determined based on the available genotype data. For Family 3, sequencing data were available for four family members, and we manually reconstructed the haplotype assuming the minimal number of recombinations. The result indicated that Family 3's haplotype was consistent with either the H2 or the H5 haplotype described in the study by Lucas et al.. On the basis of these results, our three families have at least two different haplotypes associated with the SQSTM1 mutation, indicating that this unique phenotype is not a haplotype-specific effect, as well as demonstrating that these families are not remotely related to each other. Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in @GENE$ (p.Pro392Leu) and a variant in @GENE$ (@VARIANT$). 5868303 SQSTM1;31202 TIA1;20692 rs4935;tmVar:rs4935;VariantGroup:9;CorrespondingGene:8878;RS#:4935 p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out. 8152424 DDB1 and CUL4 associated factor 17;80067;1642 FGFR1;69065 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 SOX10;5055 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -On the other hand, two missense mutations of the EPHA2 gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), @GENE$: c.1532C>T (@VARIANT$) (Fig. 6a, b). 7067772 SLC26A4;20132 EPHA2;20929 c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772 p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 1 - In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. 6161649 PTPN13;7909 MAP4K4;7442 c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566 c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 DCTN1;3011 TARDBP;7221 p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311 p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112 0 -(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.@VARIANT$, p.A2282T) vector plasmids and myc-tagged WT or mutant TTC26 (@VARIANT$, p.R50C). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and @GENE$ genes (figure 1). 7279190 FLNB;37480 TTC26;11786 R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280 p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260 0 -Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Sequence alterations were detected in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), @GENE$ (rs138172448), and DES (@VARIANT$) genes. 6180278 RYR1;68069 CAPN3;52 rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685 rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 0 -Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and @GENE$ (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. 4470809 OPTN;11085 TBK1;22742 c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281 c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769 1 -The proband described by Forlani et al. was heterozygous for HNF1A @VARIANT$ and HNF4A R80Q. Both mutations are novel and whilst a different mutation, R80W, has been reported in @GENE$, further evidence to support the pathogenicity of E508K is lacking. The siblings we describe with the HNF1A P291fsinsC and HNF4A R127W mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic. The @GENE$ P291fsinsC (c.872dup) mutation is the most common of all MODY mutations: it results in a frameshift and premature termination codon. There is no doubt over its pathogenicity and both sisters had inherited this mutation from their diabetic father. The HNF4A @VARIANT$ mutation was first described by Furuta et al. in 1997 and is the most common HNF4A mutation, reported in the literature in 15 families from multiple countries. . 4090307 HNF4A;395 HNF1A;459 E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173 R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226 0 -We identified a novel variant in the NOD2 gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R). The new @GENE$ missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. 3975370 IL10RA;1196 NOD2;11156 p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 0 -In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. 3125325 MYO7A;219 USH2A;66151 c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ @VARIANT$ and @GENE$ @VARIANT$). 5887939 CELSR1;7665 SCRIB;44228 c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 1 -(E) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in @GENE$ and c.511C>T in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained. 3842385 EDA;1896 WNT10A;22525 c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). 3842385 EDA;1896 WNT10A;22525 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G @VARIANT$) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature. 3975370 NOD2;11156 IL10RA;1196 2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 p. S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 0 -On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant @VARIANT$. The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 DUSP6;55621 SEMA7A;2678 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). 2737700 Cx31;7338 GJB2;2975 A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 - CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between @GENE$ and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2). 7549550 RIPPLY1;138181 TBX6;3389 c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129 p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444 0 -This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same @GENE$ heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in @GENE$, c.1810G>A;@VARIANT$ (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. 5505202 PROKR2;16368 FGFR1;69065 p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418 p.A604T;tmVar:p|SUB|A|604|T;HGVS:p.A604T;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644 1 -Three of the most common known pathogenic variations in two genes (USH2A and RHO) were detected among seven probands, the three commonest variants were @GENE$ c.2802T > G p.Cys934Trp (13%, 3/23), @VARIANT$ (8.7%, 2/23), and RHO c.403C > T c.403C > T (8.7%, 2/23), and all of these were known pathogenic variations. Genotype-phenotype correlations The proband of the family seven detected a compound heterozygous novel mutation in the @GENE$ gene c.1406C > G (p.Ser469Ter) and c.1498C > T (@VARIANT$). 7196472 USH2A;66151 AGBL5;11053 c.8559-2A > G;tmVar:c|SUB|A|8559-2|G;HGVS:c.8559-2A>G;VariantGroup:11;CorrespondingGene:7399;RS#:397518039(Expired) p.Arg500Cys;tmVar:p|SUB|R|500|C;HGVS:p.R500C;VariantGroup:0;CorrespondingGene:60509;RS#:1299838441 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -However, none of these signs were evident from metabolic work of the patient with @GENE$ @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of @GENE$ @VARIANT$ and NDUFS8 I126V variants remain unknown. 6072915 PHKA1;1981 GBE1;129 L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635 D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257 0 -Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-@VARIANT$, @GENE$-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers. 5578023 KCNH2;201 KCNE1;3753 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, @VARIANT$, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of @GENE$ did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-@GENE$ A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. 7067772 EphA2;20929 pendrin;20132 Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777 F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 0 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -We did not find a mutation in FGFR1 in any of the individuals carrying a mutation in @GENE$ or PROK2, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in @GENE$ exon 8 (Figure S3), which was not detected in 500 alleles from control individuals. 161730 PROKR2;16368 KAL1;55445 p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599 p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -We did not find a mutation in FGFR1 in any of the individuals carrying a mutation in PROKR2 or @GENE$, either. However, one of the patients heterozygous for the @VARIANT$ mutation in @GENE$ (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals. 161730 PROK2;9268 PROKR2;16368 p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599 p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). 6610752 LQT5;71688 KCNH2;201 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 0 -Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type @GENE$, which did not exist between @VARIANT$ FLNB and @VARIANT$ @GENE$ (figure 3D). 7279190 FLNB;37480 OFD1;2677 p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226 p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481 0 -Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ @GENE$R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001. 4853519 MAN1B1;5230 GAPDH;107053 M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While TIMP3 blocks VEGF/@GENE$ signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3). 6161649 VEGFR2;55639 RASA1;2168 c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745 p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293 0 - Digenic inheritances of GJB2/@GENE$ and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the @GENE$ locus. 4998745 MITF;4892 DFNB1;2975 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The p.R341 residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of @VARIANT$ in @GENE$ in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages. Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II). 4998745 MITF;4892 GJB2;2975 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 - CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway. 7549550 MEOX1;3326 TBX6;3389 c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491 c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682 0 -By contrast, @GENE$ variants @VARIANT$ and @VARIANT$ activated the CYP17 promoter similar to wt. Transcriptional activity of GATA4 variants on the @GENE$ promoter. 5893726 GATA4;1551 CYP17A1;73875 Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038 Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748 0 -Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for @GENE$ (Cx26) and @GENE$ (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 connexin 26;2975 connexin 31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 1 -Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). 3125325 USH2A;66151 MYO7A;219 c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 0 -20 The identified @GENE$ (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include @GENE$, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 7689793 CUX1;22551 RYR3;68151 p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849 c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 0 -Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/@GENE$ C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of TACI gene in the proband II.2. 5671988 TCF3;2408 TACI;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). 2737700 Cx31;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation. Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2). Nonetheless, recent studies proved that KIF5A variants have a role in ALS. According to earlier studies, KIF5A variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. 6707335 SIGMAR1;39965 KIF5A;55861 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 DVL3;20928 SCRIB;44228 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. 6707335 SPG11;41614 UBQLN2;81830 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. 6707335 SPG11;41614 UBQLN2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941 0 -The brother who is homozygous (II.4) for the TNFRSF13B/@GENE$ @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. 5671988 TACI;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, @VARIANT$ (c.379C>T) and a heterozygous frameshift mutation in exon 4 of @GENE$, P291fsinsC (@VARIANT$). 4090307 HNF4A;395 HNF1A;459 R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226 c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825 1 -(a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), @GENE$ p.307_308del showed a decreasing trend in molecular weight and increasing instability. However, the prediction of theoretical pI, aliphatic index and GRAVY presented no significant differences. Compared to the @GENE$ protein properties of wild-type SCN5A, SCN5A @VARIANT$ slightly increased its molecular weight and aliphatic index but reduced its instability index. 8739608 KCNH2;201 Nav1.5;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Functional impact of the rare variants The two missense @GENE$ variants (p.(H395N) and (@VARIANT$) and one of the @GENE$ amino acid substitutions (@VARIANT$) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation. 6338360 FOXC2;21091 PITX2;55454 p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism. 4470809 OPTN;11085 TBK1;22742 p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 0 -However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while @GENE$ mutation was only associated with sinoatrial node dysfunction. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN2;86984 NRXN1;21005 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys." 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). 2737700 GJB3;7338 GJB2;2975 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered. A genetic cause was sought in a child with combined multiple pituitary hormone deficiencies. The findings implicate a digenic mechanism of inheritance, with a mutation in @GENE$ and in @GENE$. Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland that is characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic or absent posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland. 5505202 PROKR2;16368 WDR11;41229 p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418 p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). 2737700 GJB2;2975 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -He had no mutations in CHD7, FGF8, @GENE$, PROK2, PROKR2, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (@VARIANT$) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease. This @GENE$ deletion was associated with exon 10 skipping, but was not sufficient to cause KS alone. 3888818 FGFR1;69065 NELF;10648 c.1159-14_22del;tmVar:c|DEL|1159-14_22|;HGVS:c.1159-14_22del;VariantGroup:12;CorrespondingGene:26012 p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218 0 -In this case, haploinsufficiency of the carboxylase activity and reduced @GENE$ functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the ABCC6 gene (@VARIANT$) and the @GENE$ gene (@VARIANT$) yet did not display any cutaneous findings are not clear. 2900916 ABCC6;55559 GGCX;639 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 -The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of @GENE$, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, Q446R, or @VARIANT$ positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of @GENE$ (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. 7067772 EphA2;20929 pendrin;20132 G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees. 6081235 GNA14;68386 MYOD1;7857 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (@VARIANT$). 3125325 CDH23;11142 USH2A;66151 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. 5868303 SQSTM1;31202 TIA1;20692 c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 0 - CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in @GENE$ was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2). 7549550 MYOD1;7857 TBX6;3389 c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129 c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444 0 -This included the variants in @GENE$ (chr6, NM_000426.3:c.380A > G (@VARIANT$); MAF 1.76 x 10-5) and @GENE$ (chr10, NM_0002211:c.1684_1686del (@VARIANT$); MAF 3.871 x 10-5), which affected amino acid residues that were found to be highly conserved across species (Fig. 1). 8474709 LAMA2;37306 LOXL4;12977 p.Thr127Ala;tmVar:p|SUB|T|127|A;HGVS:p.T127A;VariantGroup:0;CorrespondingGene:3908 p.Glu562del;tmVar:p|DEL|562|E;HGVS:p.562delE;VariantGroup:4;CorrespondingGene:84171 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$). 5887939 CELSR1;7665 FAT4;14377 c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776 c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329 0 -Specifically, the mother and her twin sister were heterozygous for the @GENE$ missense mutation @VARIANT$ and the ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. However, the proband's younger brother and father were heterozygous carriers of the p.S300F mutation in the GGCX gene while they also carried the p.R1141X mutation in the @GENE$ gene; they did not display any signs of cutaneous findings or hematologic disorder. 2900916 GGCX;639 ABCC6;55559 p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with @GENE$ p.I2547T and SETX @VARIANT$). 4293318 ANG;74385 SETX;41003 p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583 p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 ANG;74385 TARDBP;7221 p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. 6081235 CACNA1A;56383 ATP2A3;69131 p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346 p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011 0 -A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous. 5445258 ALS2;23264 TARDBP;7221 P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513 A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343 1 -The c.229C>T (@VARIANT$) variant in S100A3 and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2. Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder. 6637284 S100A3;2223 S100A13;7523 p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 - Mutation detection in the family (a) Identification of the recurrent nonsense mutation @VARIANT$ in the @GENE$ gene. Note the heterozygous C T transition substitution at nucleotide position 3421 (arrow). (b, d) Identification of missense mutations p.V255M and @VARIANT$ in the @GENE$ gene. 2900916 ABCC6;55559 GGCX;639 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 -Pathogenic effects of GBE1 @VARIANT$ and @GENE$ I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the RYR1 p.T4823 M variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with @GENE$ p. R498L, previously reported in a single MHS subject. However, the frequency of this variant in the general population is about 20-fold higher than the frequencies of pathogenic CACNA1S variants associated with MHS. It is also important to note that the diagnostic test for MH has a high false-positive rate of 22%, which raises the possibility that MHS diagnosis in subject R462 may be false. Based on these results, we also ruled out a pathogenic role of the CACNA1S @VARIANT$ variant in MH. 6072915 NDUFS8;1867 CACNA1S;37257 D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257 p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SOX10;5055 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Two potential disease-causing mutations were identified: (d) ENAM: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) LAMA3 missense mutation c.1559G>A/@VARIANT$. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (@GENE$ and @GENE$) mutations. 6785452 ENAM;9698 LAMA3;18279 c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801 p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909 1 - CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in @GENE$ was also identified. Although no direct interaction between @GENE$ and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2). 7549550 MYOD1;7857 RIPPLY1;138181 c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129 p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444 0 -Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, DUOXA2 and @GENE$). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, p.S309P and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The @GENE$ variant p.R450H was a recurrent inactivating mutation and p.C176R and @VARIANT$ were novel. 7248516 TPO;461 TSHR;315 p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605 p.K618;tmVar:p|Allele|K|618;VariantGroup:4;CorrespondingGene:7253 0 -Digenic Inheritance of @GENE$ and @GENE$ Mutations in Patient with Infantile Dilated Cardiomyopathy Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, @VARIANT$) and a known DCM mutation in MYH7 (c.2770G > A; @VARIANT$). 6359299 LAMA4;37604 MYH7;68044 p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057 p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034 1 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I). 4293318 ANG;74385 TAF15;131088 p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953 p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127 0 -Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature. The three-missense variants were searched for in both parents to check their pattern of inheritance. The mother carried the three variants (@VARIANT$, S159G and G351R) observed in the patient, while the father results heterozygous only for the G351R variant (Figure 1). The new @GENE$ missense variant was searched for in 60 anonymous healthy Italian donors to confirm if it was not a polymorphism, but a true mutation: no variant has been found. 3975370 IL10RA;1196 NOD2;11156 p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 0 -The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. 6707335 CCNF;1335 alsin;23264 R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 0 -Most variants were included in the databases or reported in previous studies, except for one heterozygous variant in TSHR (i.e., @VARIANT$) that was novel. Interestingly, we found that variants in the genes causing DH were more common than those in the genes causing TD (87.9% versus 12.1%). We further observed that, among the 58 identified variants, the genes with the most frequent variants were DUOX2 (70.7%), followed by TSHR (12.1%), DUOXA2 (10.3%), and @GENE$ (5.2%) (Figure 1). In addition, seven of these variants were detected in more than one patient: five DUOX2 variants, one DUOXA2 variant, and one @GENE$ variant (Table 2). We found that these variants accounted for 53.4% (31/58) of the total variants, with the @VARIANT$ and p.Arg1110Gln mutations in DUOX2 constituting the predominant sites in the present cohort. 8446595 TPO;461 TSHR;315 p. Ala579Val;tmVar:p|SUB|A|579|V;HGVS:p.A579V;VariantGroup:31;CorrespondingGene:7253 p.Lys530*;tmVar:p|SUB|K|530|*;HGVS:p.K530*;VariantGroup:34;CorrespondingGene:50506 0 -There is a splicing site mutation c.1339 + 3A>T in @GENE$, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes. 6565573 COL4A5;133559 COL4A3;68033 c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174 Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 0 -Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons. 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 - A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -The changed site (position 307) of @GENE$ p.307_308del was located close to the largest hydrophobic region of the protein (Figure 5a). The hydrophobicity of predicted amino acid residues and adjacent sequences was significantly weakened, which probably made the largest hydrophobic domain (position 303) disorganized. The changed site of the SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant (Figure 5b). Transmembrane structure analysis (Table 4) showed that the mutant site of KCNH2 @VARIANT$ was located in the protein's transmembrane domain, which suggested that the site may be associated with potential functions, including protein localization, substances transportation, ion channels, and others. Phosphorylation analysis of KCNH2 p.307_308del showed that this mutation caused amino acid residues near position 309 dephosphorylation. The result indicated that KCNH2 p.307_308del might impact the catalytic efficiency of protein. However, there was no significant change in protein phosphorylation for @GENE$ @VARIANT$ (Table 4). 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN2;86984 NRXN1;21005 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the @GENE$ repeat expansion or a missense variant in SOD1 in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 C9ORF72;10137 VAPB;36163 p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583 p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390 0 -However, loss-of-function mutations in @GENE$ have not hitherto been described, and its role in thyroid biology remains undefined. Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a @GENE$ homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. 5587079 DUOX1;68136 DUOX2;9689 p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe). 6567512 BBS1;11641 BBS6;10318 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 0 -In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. 6707335 GRN;1577 SQSTM1;31202 P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866 0 -The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. 3842385 WNT10A;22525 EDA;1896 c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326 Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother. 8152424 DDB1 and CUL4 associated factor 17;80067;1642 DMXL2;41022 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930 1 - A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. 6707335 ALS2;23264 MATR3;7830 R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 FZD;8321;8323 FAT4;14377 c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625 c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776 0 -We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). 2737700 GJB2;2975 GJB3;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/Cx31 connexons. 2737700 GJB3;7338 Cx26;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes. 6565573 COL4A5;133559 COL4A3;68033 Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286 0 -Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, @GENE$, @GENE$, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases. 6098846 TG;2430 DUOX2;9689 p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376 p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197 0 -Therefore, in this study, @GENE$ @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD. Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature. 3975370 IL10RA;1196 IL10RB;523 p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 0 -In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2). 6161649 ENG;92 SCUBE2;36383 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 1 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 DCTN1;3011 TARDBP;7221 p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583 p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459 0 -It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed. 5611365 CYP1B1;68035 MYOC;220 p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012 p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636 0 -SCAP-c.3035C>T (p.Ala1012Val) variant impaired the negative feedback mechanism of cholesterol synthesize in H293T cell lines @GENE$-c.3035C>T (p.Ala1012Val) variant was introduced into H293T cell lines by CRISPR-Cas9 methodology. After incubated with medium A (as described in the materials and methods section) for 6 hours, the wild-type goups showed a significant different distribution of SREBP-2 in cytoplasm and nucleus, (Figure 4A) while the SCAP-mutated groups shows no such difference (Figure 4B). These phenomenon indicate that the mutated SCAP-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-c.1103C>T (@VARIANT$) variant impaired the catabolism of ADMA in EA. 5725008 SCAP;8160 AGXT2;12887 p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, @GENE$ @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 PTK7;43672 SCRIB;44228 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256 0 -(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999. 3975370 IL10RA;1196 NOD2;11156 c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322 c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 CACNA1A;56383 TRPV4;11003 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$). 3888818 NELF;10648 TACR3;824 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation. 6610752 KCNE2;71688 KCNH2;201 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 0 -On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f). 7067772 EphA2;20929 ephrin-B2;3019 Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 0 -DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant @GENE$ allele from his mother; WNT10A mutations in the parents could not be analyzed. 3842385 WNT10A;22525 EDA;1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous @GENE$ p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a). 8739608 KCNH2;201 SCN5A;22738 c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 - Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. 6707335 SPG11;41614 UBQLN2;81830 L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152 M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 SOX10;5055 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. 6707335 GRN;1577 SQSTM1;31202 C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519 P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866 0 -On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and @GENE$ S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. 7067772 EphA2;20929 pendrin;20132 Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The @VARIANT$ and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. 6707335 GRN;1577 SQSTM1;31202 P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 0 -We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 GJB2;2975 GJB3;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 KAL1;55445 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 REEP4;11888 VPS13C;41188 p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 0 - In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing BMP/TGF-beta signalling. 6161649 MAP4K4;7442 ENG;92 c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566 p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 0 -Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 PROK2;9268 p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 0 -Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 KAL1;55445 FGFR1;69065 p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser." 3842385 WNT10A;22525 EDA;1896 Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Proband 17 inherited @GENE$ p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. 8152424 CHD7;19067 CDON;22996 p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 - Results We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and @GENE$ @VARIANT$ (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter-defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with @GENE$ @VARIANT$ as a de novo mutation, but not existed in other family members. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 SOX10;5055 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -R85C in @GENE$ (MIM 607123; NM_144773.2; @VARIANT$) inherited from an unaffected mother and @VARIANT$;p.I436V in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1). 5505202 PROKR2;16368 WDR11;41229 rs141090506;tmVar:rs141090506;VariantGroup:1;CorrespondingGene:128674;RS#:141090506 c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 1 -Her mother with c.1339 + 3A>T in COL4A5 and her father with a missense mutation @VARIANT$ in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes. 6565573 COL4A4;20071 COL4A3;68033 c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174 Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -"The other two @GENE$ variants, c.2450C>G (p.Ser817Cys) and @VARIANT$ (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the @GENE$ mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance." 8621929 LRP6;1747 WNT10A;22525 c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 TEK;397 CYP1B1;68035 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 1 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). 6610752 LQT6;71688 LQT2;201 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 0 -KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNQ1;85014 KCNE1;3753 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys." 3842385 WNT10A;22525 EDA;1896 Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. 5953556 TEK;397 CYP1B1;68035 p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -He also had a @GENE$ deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, @GENE$, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R. 3888818 KAL1;55445 PROK2;9268 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$). 5887939 CELSR2;1078 FZD6;2617 c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776 c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329 0 - Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene. 6707335 SPG11;41614 UBQLN2;81830 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. 3842385 EDA;1896 WNT10A;22525 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Further molecular studies are needed to prove the deleterious character of the @GENE$ Lys205del variant. Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. 8446458 PROKR2;16368 SEMA7A;2678 Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050 Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 0 -RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). 2737700 Cx26;2975 Cx31;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation. 6610752 LQT2;201 LQT6;71688 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 0 -M, mother; F, father; S1, sister; all unaffected and heterozygous for the @GENE$ @VARIANT$ mutation. Further biochemical evaluation Urine iodine measurements were not available at diagnosis, but subsequent spot measurements suggested mild (P2, 73.9 microg/L) to moderate (P1, 45.6 microg/L) iodine deficiency (RR 100 to 700 microg/L). Moderate iodine deficiency in association with double heterozygosity for DUOX1 and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). 5587079 DUOX1;68136 DUOX2;9689 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in MYO7A. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father. 3949687 MYO7A;219 PCDH15;23401 c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of @GENE$. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of @GENE$. Direct sequence analysis showing the 580G>A (@VARIANT$) mutation (i and n) and WT allele (j and o) of GJB3. 2737700 GJB2;2975 GJB3;7338 299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$). 4293318 ANG;74385 SETX;41003 p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953 p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953 0 -Since @GENE$ localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ @GENE$ and @VARIANT$ OFD1 (figure 3D). 7279190 OFD1;2677 FLNB;37480 p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226 p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481 0 -In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. 3125325 USH1G;56113 MYO7A;219 c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B). 3842385 WNT10A;22525 EDA;1896 c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326 Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 0 -To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be @GENE$, DFNB3, and @GENE$, respectively. Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES. 4998745 DFNB7/11;23670 DFNB16;15401 p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234 p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681 0 -Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes. 4470809 OPTN;11085 TBK1;22742 c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 0 -Most had C9orf72 repeat expansion combined with another mutation (e.g. VCP R155H or @GENE$ @VARIANT$; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in @GENE$ and A90V in TARDBP. 5445258 TARDBP;7221 ALS2;23264 A321V;tmVar:p|SUB|A|321|V;HGVS:p.A321V;VariantGroup:27;CorrespondingGene:23435 P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 TACR3;824 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 - Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein. 6707335 ubiquilin-2;81830 FUS;2521 L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152 M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941 0 -The synonymous change p.(@VARIANT$) (rs138318843) was carried by four patients (3%), showing a 4- to 10-fold increased frequency compared with that reported in 1000 Genomes and ExAC databases (0.3% and 0.7%, respectively, Table 1). The variant was associated with variable age at diagnosis and IOPs, ranging from two and a half months to three years and from 22 to 45 mmHg, respectively (Table 2). p.(S36S) carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at @GENE$-AS1 intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on FOXC2 and a modifier outcome on both @GENE$ and the overlapping promoter. 6338360 FOXC2;21091 FOXC2-AS1;103752587;2303;5729 S36S;tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260 n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$). 6567512 BBS1;11641 BBS7;12395 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). 6161649 BMP;55955 ENG;92 p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 0 -Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, R127W (@VARIANT$) and a heterozygous frameshift mutation in exon 4 of HNF1A, P291fsinsC (@VARIANT$). @GENE$ therapy was completely discontinued and she was started on glipizide (1.25 mg once daily) with the dose titrated to 2.5 mg once daily based on blood sugar checks, with weekly blood sugar reviews and close support from a diabetes specialist nurse practitioner. 4090307 HNF4A;395 Insulin;173 c.379C>T;tmVar:c|SUB|C|379|T;HGVS:c.379C>T;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226 c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825 0 -In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). 2737700 GJB3;7338 GJB2;2975 A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 - Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, p.Q1916R) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that @VARIANT$ is highly conserved across mammals (red font). (C) Topology model of the alpha-subunit of LTCC. The localization of the mutation is indicated by a red dot, and polymorphisms are indicated by green dots. (D) A variant (c.3578G>A, @VARIANT$) in SCN5A. 5426766 CACNA1C;55484 SCN5A;22738 Q1916;tmVar:Q1916;VariantGroup:8;CorrespondingGene:775 p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 0 -While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations. 7067772 EphA2;20929 pendrin;20132 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (@VARIANT$) exhibit perturbed interaction. 5953556 TEK;397 CYP1B1;68035 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 1 - Results We identified the digenic heterozygous mutations of @GENE$ @VARIANT$ (NM_001204798, c.921_923del) and @GENE$ p.R1865H (NM_001160160, @VARIANT$) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 1 -Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and @GENE$ @VARIANT$, implying that the deleterious variants in @GENE$ act together with other variants to cause IHH through a digenic/oligogenic model. 8152424 FGFR1;69065 CCDC88C;18903 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, @GENE$, and BCL9L) as well. 7877624 TYRO3;4585 BCL9;3191 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 - In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in PTPN13 (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. 6161649 ENG;92 MAP4K4;7442 p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566 p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 0 -CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ @VARIANT$ mutation, but not the TNFRSF13B/TACI C104R mutation. 5671988 TACI;49320 TCF3;2408 c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and @VARIANT$; @VARIANT$ of TACR3). 3888818 KAL1;55445 NELF;10648 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Based on both clinical and laboratory quantification, it appears neither the TNFRSF13B/@GENE$ @VARIANT$ mutation nor the @GENE$ @VARIANT$ mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband. 5671988 TACI;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 1 -Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. 4470809 TANK-binding kinase 1;22742 OPTN;11085 p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 0 -Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN2;86984 NRXN1;21005 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). 2737700 GJB2;2975 GJB3;7338 299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, @VARIANT$), LAMA2 p.A961T (NM_000426, @VARIANT$), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). 8739608 SCN5A;22738 KCNH2;201 c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation. 6610752 LQT2;201 LQT6;71688 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug @GENE$-WT or 1 mug KCNQ1-@VARIANT$ + 1 mug KCNE1-WT) or 3 mug (1.5 mug KCNH2-WT + 1.5 mug @GENE$-@VARIANT$ or 1.5 mug KCNH2-WT + 1.5 mug empty vector) plasmid per dish were used. 5578023 KCNE1;3753 KCNH2;201 c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757 0 -However, when combined with the @GENE$ mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of LRP6 and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. 8621929 LRP6;1747 WNT10A;22525 Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The results showed that, in addition to the @GENE$ gene variant [p.(@VARIANT$)], a second variant in c.2803C > T in the @GENE$ gene was involved in the second highest number of pathogenic digenic combinations (15%), with 18 other variants in 13 genes. The CCDC141 variant was found at a homozygous state in the patient HH1 and at a heterozygous state in the asymptomatic cases. Our analysis indicated that the zygosity state of the @VARIANT$ variant in the CCDC141 gene considerably influenced the rate of pathogenic combinations. 8446458 PROKR2;16368 CCDC141;52149 Pro290Ser;tmVar:p|SUB|P|290|S;HGVS:p.P290S;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257 c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885 0 -SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and @GENE$ mutations. KCNH2 @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees. 6081235 UNC13B;31376 MRPL15;32210 p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 0 -The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2. 5671988 TNFRSF13B;49320 TCF3;2408 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor @GENE$. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation @VARIANT$, but no effect on transactivation activity on the CYP17 promoter for @GENE$ variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only Gly221 and Cys238 are close to Zn binding sites. The Gly221 is not directly involved in Zn binding but is situated next to Cys220 which binds the Zn atom, and therefore, the mutation Gly221Arg will disrupt the Zn binding, leading to a non-functional GATA4. The Cys238 binds Zn and its mutation to arginine leads to loss of Zn binding (Figure 4). GATA4 regulates the expression of multiple genes coding for hormones or components of the steroidogenic pathway during testis development and function. In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development. 5893726 FOG2;8008 GATA4;1551 p.Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626 p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). 2737700 GJB2;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -A list of these numerous @GENE$ mutations discovered in patients with CHD so far is provided in Table S2 in Supplementary Material. For a more comprehensive review of the role of GATA4 in CHD we refer to Ref.. By contrast, the few GATA4 missense mutations found in 46,XY DSD individuals with or without CHD are all located in the N-terminal zinc finger domain, which is responsible for DNA binding and interaction with cofactors. Functional characterization of GATA4 variants with respect to the 46,XY DSD phenotype has only been performed for the p.Gly221Arg mutation so far. In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor @GENE$. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the CYP17 promoter for GATA4 variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only @VARIANT$ and @VARIANT$ are close to Zn binding sites. 5893726 GATA4;1551 FOG2;8008 Gly221;tmVar:p|Allele|G|221;VariantGroup:4;RS#:398122402(Expired) Cys238;tmVar:p|Allele|C|238;VariantGroup:0;CorrespondingGene:2626 0 -We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 CELSR1;7665 PTK7;43672 c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. 5953556 TEK;397 CYP1B1;68035 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Merged images showing pro-@GENE$ colocalization with @GENE$ in wild-type (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double-homozygous (L) fibroblasts. 4853519 COL1A1;73874 TGN38;136490 M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, TG, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases. Although dual oxidase 1 (@GENE$) and dual oxidase maturation factor 1 (@GENE$) have established roles in thyroid hormone production, relevant mutations associated with CH have not been found. 6098846 DUOX1;68136 DUOXA1;16043 p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552 p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376 0 -" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in WNT10A (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The LRP6 c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS. It was predicted to be ""possibly damaging"", with a PolyPhen-2 score of 0.767. The WNT10A mutation (c.499G>C, rs148714379), while being rare (MAF = 0.0003), was categorized as a benign variant (PolyPhen-2 score = 0.087). Segregation analysis showed that the father carried the two LRP6 variants, while the mother and the younger sister were both heterozygotes for the @GENE$ mutation. These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and WNT10A." 8621929 WNT10A;22525 LRP6;1747 c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. 6081235 CACNA1A;56383 REEP4;11888 c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773 c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211 0 -To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, DFNB3, and @GENE$, respectively. Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES. 4998745 DFNB16;15401 Wolfram syndrome 1;4380 p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234 p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681 0 -These phenomenon indicate that the mutated SCAP-@VARIANT$ (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated @GENE$ coding protein. @GENE$-@VARIANT$ (p.Ala338Val) variant impaired the catabolism of ADMA in EA. 5725008 SCAP;8160 AGXT2;12887 c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937 c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG @VARIANT$, and @GENE$ p.T1249I. 4293318 SOD1;392 DCTN1;3011 p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311 p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112 0 -Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; p.Val134Gly, at 0.0008%; @VARIANT$ at 0.2%; and @GENE$ @VARIANT$ at 0.0008%). Discussion The overall prevalence of @GENE$ mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. 5527354 PROKR2;16368 GNRHR;350 p.Arg262Gln;tmVar:p|SUB|R|262|Q;HGVS:p.R262Q;VariantGroup:5;CorrespondingGene:2798;RS#:104893837;CA#:130198 p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400 0 -A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in TARDBP. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous. Furthermore, the @GENE$ variant has been previously identified in controls and has unclear status, although it is associated with abnormal localization and aggregation of TARDBP. 5445258 ALS2;23264 TARDBP;7221 P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513 A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343 0 -Four genes (including AGXT2, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-@VARIANT$ (p.Ala1012Val) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies. 5725008 SCAP;8160 AGXT2;12887 c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 -Genotypes: @GENE$ p.Thr1100Met (@VARIANT$; blue); @GENE$ p.Tyr179Cys (@VARIANT$; green); -, wild type. 7689793 MSH6;149 MUTYH;8156 T1100M;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473 Y179C;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 KAL1;55445 TACR3;824 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$). 3888818 NELF;10648 TACR3;824 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 TYRO3;4585 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 MITF;4892 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -@VARIANT$ carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at @GENE$-AS1 intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on FOXC2 and a modifier outcome on both @GENE$ and the overlapping promoter. 6338360 FOXC2;21091 FOXC2-AS1;103752587;2303;5729 p.(S36S);tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260 n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 DVL3;20928 FAT4;14377 c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 0 -DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). 4998745 gap junction protein beta 6;4936 GJB3;7338 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Note that subject II:1 in family PCG-133 was diagnosed at the age of 3 months and carried the de novo @VARIANT$ PITX2 variant, whereas his brother, who did not carry this variant, was diagnosed at the age of 10 years. The proband in family PCG-139 also carried a rare @GENE$ variant (p.(A188T)) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, @GENE$: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases. 6338360 PITX2;55454 CYP1B1;68035 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 0 - Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in @GENE$, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. 4998745 GJB3;7338 GJB2;2975 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -(D) Validation by Sanger sequencing of the identified @GENE$ @VARIANT$;7117C>T] and @GENE$ @VARIANT$ mutations in the affected individual, the unaffected sibling and her parents. 5967407 RP1L1;105870 C2orf71;19792 c.[326_327insT;tmVar:c|INS|326_327|T;HGVS:c.326_327insT;VariantGroup:0;CorrespondingGene:94137;RS#:771427543;CA#:4625758 c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678 1 -GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, @VARIANT$ (c.100C>T) (rs121908073), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1). 4998745 GJB2;2975 TMC1;23670 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R34X;tmVar:p|SUB|R|34|X;HGVS:p.R34X;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$). 4293318 ANG;74385 VAPB;36163 p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953 p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953 0 -The study revealed @GENE$ gene mutations in a majority of our cohort (33%), in accordance with the percentages already reported in the literature. Interestingly, we found just one patient with variants in BBS1, the most frequently detected gene in BBS patients. We identified a novel variant in BBS1 patient #10 c.1285dup (@VARIANT$) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic. A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, was identified in patient #3. BBS1, BBS2 and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. 6567512 BBS10;49781 BBS7;12395 p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582 p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583 0 - In a second example, we identified a monoallelic change in @GENE$ (c.G680A, @VARIANT$, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014). 5765430 SRD5A2;37292 SF1;138518 p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681 single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536 1 -@GENE$-@VARIANT$ affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, KCNE1-p.G38S is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the @GENE$-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents. 5578023 KCNH2;201 KCNE1;3753 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). 5887939 PRICKLE4;22752 DVL3;20928 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, p.Tyr27His), MBD5 (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited. 6371743 GAMT;32089 NRXN1;21005 p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 HS1BP3;10980 DNAH17;72102 c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211 p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 0 -@GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). 6161649 SCUBE2;36383 VEGFR2;55639 c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745 c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293 0 -In our study, we identified four genetic variants in three genes (KCNQ1-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$). 5578023 KCNH2;201 KCNE1;3753 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 1 -We did not find a mutation in @GENE$ in any of the individuals carrying a mutation in @GENE$ or PROK2, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals. 161730 FGFR1;69065 PROKR2;16368 p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599 p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972 0 -We found eight probands (6.0%) who carried four rare @GENE$ variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare @GENE$ variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, @VARIANT$) have not been previously identified. 6338360 FOXC2;21091 PITX2;55454 p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 TACR3;824 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 TACR3;824 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 0 - Molecular Data All three probands carry two heterozygous variants: SQSTM1, @VARIANT$ (p.Pro392Leu), and @GENE$, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The TIA1 variant and @GENE$ variants have been reported in multiple databases. 5868303 TIA1;20692 SQSTM1;31202 c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 0 - A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3. @GENE$, BBS2 and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. 6567512 BBS1;11641 BBS7;12395 p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583 c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212 0 -Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a). 2737700 GJB2;2975 GJB3;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. 5953556 CYP1B1;68035 TEK;397 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 - Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). This mutation was not present in 100 control alleles by restriction enzyme digestion and/or by direct nucleotide sequencing (Fig. 3c). Secondly, a single nucleotide substitution (c.927C T) resulting in substitution of a serine by phenylalanine in position 300 (@VARIANT$) was detected (Fig. 3d). 2900916 GGCX;639 VKORC1;11416 c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 - Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES. 4998745 GJB2;2975 WFS1;4380 p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234 p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681 1 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 ANG;74385 TARDBP;7221 p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112 p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of @GENE$). 3888818 NELF;10648 TACR3;824 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Two novel @GENE$ frameshift mutations were identified. A single-nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (@VARIANT$/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/@VARIANT$) that cosegregated with both the AI phenotype and the ENAM mutation. 6785452 ENAM;9698 LAMA3;18279 c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801 p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909 0 -Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). 6161649 ENG;92 SCUBE2;36383 p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 1 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDNRB;89 PAX3;22494 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the GGCX gene (@VARIANT$) yet did not display any cutaneous findings are not clear. Specifically, while both GGCX mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the p.S300F mutation was more pronounced than that of p.V255M. In this context, it should be noted that the substrate employed in the carboxylase assay is a pentapeptide, Phe-Leu-Glu-Glu-Leu, and it is possible that the activity measurements if done on full-length @GENE$ as substrate would show differential activity with these two mutant enzymes. 2900916 ABCC6;55559 MGP;693 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 -Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism. 4470809 OPTN;11085 TBK1;22742 p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970 0 -Using SIFT and PolyPhen, the @VARIANT$ variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (p.Asn118Ser) in MFSD8. 7463850 SLC9A6;55971 EHMT1;11698 c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465 p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene. 6707335 SPG11;41614 UBQLN2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941 0 -The large genomic rearrangement in @GENE$ previously reported by Le Guedard et al. was not detected in this group of patients. Three pathogenic or presumably pathogenic mutations in @GENE$ were found in three patients, specifically, an already reported nonsense mutation (@VARIANT$), a novel nucleotide duplication (c.84dupC; @VARIANT$), and a novel sequence variant (c.46C>G; p.L16V). 3125325 PCDH15;23401 USH1G;56113 p.W38X;tmVar:p|SUB|W|38|X;HGVS:p.W38X;VariantGroup:91;CorrespondingGene:124590;RS#:104894652;CA#:252490 p.D29fsX29;tmVar:p|FS|D|29||29;HGVS:p.D29fsX29;VariantGroup:279;CorrespondingGene:26839 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. 8152424 DDB1 and CUL4 associated factor 17;80067;1642 FGFR1;69065 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Interestingly, it has been reported that the @GENE$-@VARIANT$ variant, located in the PAS domain, reaches the cell surface, but it remains in the immature form and is non-conducting. On the contrary, the functionality of the KCNQ1-p.R583H channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNE1;3753 p.C66G;tmVar:p|SUB|C|66|G;HGVS:p.C66G;VariantGroup:2;CorrespondingGene:3757;RS#:199473416;CA#:6132 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A. 3125325 MYO7A;219 USH1C;77476 c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (c.1823-1G>C), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) . 5587079 DUOX1;68136 DUOX2;9689 c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3). 3888818 KAL1;55445 NELF;10648 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b). 7067772 EPHA2;20929 SLC26A4;20132 p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772 c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 0 -The SLC20A2 c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the PDGFRB c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions. Accordingly, the @GENE$ heterozygous mutation may have played an essential role in promoting the phenotypes of the proband, who showed more extensive brain calcification and headaches significantly ahead of the typical onset age between 30 and 60 years (Wang et al., 2015). To the best of our knowledge, the proband with both @GENE$ and PDGFRB variants in this study is the first reported case resulting from two known pathogenic genes, providing new proof for the digenic effect on clinical heterogeneity among PFBC patients. 8172206 PDGFRB;1960 SLC20A2;68531 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d). 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro. 4470809 TBK1;22742 OPTN;11085 c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281 p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 0 -Four genes (including AGXT2, ZFHX3, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies. 5725008 TCF4;2407 SCAP;8160 c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and @GENE$ c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 FZD6;2617 CELSR2;1078 c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 - Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. 4998745 GJB2;2975 MITF;4892 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -On the other hand, EphA2 overexpression did not affect localization of @VARIANT$. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f). 7067772 pendrin;20132 ephrin-B2;3019 G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), @GENE$ (c.46C>G; p.L16V) and USH2A (@VARIANT$). 3125325 MYO7A;219 USH1G;56113 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -To examine whether these mutations affect the ligand-binding specificity of @GENE$ to ephrin-A and ephrin-B, a pull down assay was performed with HEK293T cells due to their low level of endogenous EphA2 expression (Supplementary Fig 7a, b). While tagged versions of EphA2 G355R and EphA2 T511M were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down EphA2 G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 @VARIANT$ and EphA2 T511M with @GENE$ induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d). Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum. 7067772 EphA2;20929 pendrin;20132 G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329 H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307 0 -Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 FGFR1;69065 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b). These EPHA2 mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying c.1300G>A of SLC26A4 was previously reported. She is 22-years-old and presented congenital bilateral sensorineural hearing loss, goitre and skin disorders, while her brother, sister and parents were healthy and did not show such symptoms (Fig. 6a). Another patient carrying @VARIANT$ of SLC26A4 is 14-years-old and exhibited progressive, symmetrical sensorineural hearing loss and goitre (Fig. 6c). Her mother was healthy and carries a mutation of the @GENE$ gene but not the @GENE$ gene (Fig. 6b). 7067772 EPHA2;20929 SLC26A4;20132 c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329 c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDNRB;89 MITF;4892 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 TACR3;824 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Similarly, reduced expression of @GENE$/E2A has been implicated in equine CVID. There is thus strong support from human, murine and equine studies for the pathogenicity of the TCF3 @VARIANT$ mutation in our family. Our study also offers new insights into the role of TNFRSF13B/TACI mutations in the pathogenesis of CVID. The C104R mutant is a low frequency variant in population databases (0.32% in Exome Aggregation Consortium) and although earlier publications considered this variant to be disease-causing and expressed in up to 10% of CVID patient cohorts, it, and other TNFRSF13B/TACI variants were subsequently found to be present in ~2% of healthy control populations. Although functional studies of C104R mutant alleles have demonstrable defects in B-cell development, switching and differentiation, it is considered a risk allele for CVID, with a relative risk of 4.2 and it has long been speculated that second mutations may be identified in these families. This study is the first demonstration of such digenic inheritance in a CVID-like disorder. In this family, the TNFRSF13B/@GENE$ @VARIANT$ mutation appears to demonstrate a gene dosage effect on serum IgG levels. 5671988 TCF3;100147220 TACI;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 KAL1;55445 NELF;10648 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 SOX10;5055 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (@VARIANT$) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient. 6098846 DUOX2;9689 DUOXA2;57037 p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915 p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391 0 -For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (@VARIANT$ or p.R885Q). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (p.R110Q or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, @GENE$, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases. Although @GENE$ (DUOX1) and dual oxidase maturation factor 1 (DUOXA1) have established roles in thyroid hormone production, relevant mutations associated with CH have not been found. 6098846 TG;2430 dual oxidase 1;68136 p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376 p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. 5953556 CYP1B1;68035 TEK;397 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-@GENE$ G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). 5953556 TEK;397 CYP1B1;68035 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, @VARIANT$, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. 3125325 USH1C;77476 USH2A;66151 c.494C>T;tmVar:c|SUB|C|494|T;HGVS:c.494C>T;VariantGroup:185;CorrespondingGene:4647;RS#:111033174;CA#:278676 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 CACNA1A;56383 DNAH17;72102 p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 0 -Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (@VARIANT$, at 0.2%; p.Val134Gly, at 0.0008%; p.Arg262Gln at 0.2%; and PROKR2 @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/@GENE$) heterozygous mutation. 5527354 GNRHR;350 PROKR2;16368 p.Gln106Arg;tmVar:p|SUB|Q|106|R;HGVS:p.Q106R;VariantGroup:3;CorrespondingGene:2798;RS#:104893836;CA#:130197 p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400 0 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 PROK2;9268 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 DNAH17;72102 UNC13B;31376 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and @GENE$/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. 5671988 TCF3;2408 TNFRSF13B;49320 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. 2737700 Cx26;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. 5953556 CYP1B1;68035 TEK;397 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -@VARIANT$ might affect the normal splicing of exons in the @GENE$ gene, and the novel variant c.306G > C (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the PROKR2 gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (@VARIANT$) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. The hot spot variant c.533G > C (p. Trp178Ser) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity. The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the FGF/@GENE$ signalling pathway. 8796337 PROK2;9268 FGFR1;69065 c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675 p. Arg164Gln;tmVar:p|SUB|R|164|Q;HGVS:p.R164Q;VariantGroup:3;CorrespondingGene:128674;RS#:751875578;CA#:311167332 0 -Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 DNAH17;72102 TRPV4;11003 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of @GENE$ (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary @GENE$-binding site. 5953556 TEK;397 CYP1B1;68035 A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340 0 -Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: @VARIANT$, p.Thr1100Met) and MUTYH (NM_001128425.1: c.536A > G, p.Tyr179Cys) genes, while the other 20 genes could not be clearly linked to cancer predisposition. The identified MSH6 variant was classified as a variant of uncertain significance (VUS) in the Leiden Open Variant Database and the InSiGHT DNA Variant Database. 14 , 15 The @GENE$ variant is the most common pathogenic variant found in the Netherlands. 2 The digenic inheritance of MSH6 and MUTYH variants. A, The pedigree shows the coinheritance of the monoallelic variants which encode @GENE$ p.Thr1100Met and MUTYH @VARIANT$ in a family affected by colorectal cancer. 7689793 MUTYH;8156 MSH6;149 c.3299C > T;tmVar:c|SUB|C|3299|T;HGVS:c.3299C>T;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473 p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475 0 - Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B). 8306687 GCK;55440 HNF1A;459 c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645 p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336 1 -@GENE$ @VARIANT$ and @GENE$ @VARIANT$ of the proband were validated as positive by Sanger sequencing. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 1 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene. 6707335 ALS2;23264 DYNC1H1;1053 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. 6707335 SPG11;41614 UBQLN2;81830 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152 0 - @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene. 6707335 MATR3;7830 DYNC1H1;1053 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3). 3888818 KAL1;55445 NELF;10648 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 0 -Sequence alterations were detected in the @GENE$ (@VARIANT$), @GENE$ (rs143445685), CAPN3 (rs138172448), and DES (@VARIANT$) genes. 6180278 COL6A3;37917 RYR1;68069 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 SOD1;392 TARDBP;7221 p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311 p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112 0 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 PROK2;9268 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730 0 -Limb Girdle Muscular Dystrophy due to Digenic Inheritance of @GENE$ and @GENE$ Mutations We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (@VARIANT$), RYR1 (rs143445685), CAPN3 (@VARIANT$), and DES (rs144901249) genes. 6180278 DES;56469 CAPN3;52 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, @VARIANT$), all of which were inherited. 6371743 MBD5;81861 NRXN1;21005 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; rs7673715) c.1226A>G; @VARIANT$ and @GENE$ (MIM 600509; NM_000352.4; rs151344623) @VARIANT$ mutations. 5505202 GBA;68040 ABCC8;68048 p.N409S;tmVar:p|SUB|N|409|S;HGVS:p.N409S;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767 c.3989-9G>A;tmVar:c|SUB|G|3989-9|A;HGVS:c.3989-9G>A;VariantGroup:4;CorrespondingGene:6833;RS#:151344623;CA#:233276 1 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 TACR3;824 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 - Digenic inheritances of GJB2/@GENE$ and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus. 4998745 MITF;4892 GJB6;4936 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. The @GENE$ p.(Asn1075Ser) mutation substitutes highly-conserved asparagine with serine, which is predicted to destabilize the protein structure. 8621929 WNT10A;22525 LRP6;1747 Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 0 -Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNE1;3753 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ @GENE$R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001. 4853519 MAN1B1;5230 GAPDH;107053 M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient. 6098846 DUOX2;9689 DUOXA2;57037 p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155 c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064 0 -"Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees. 6081235 ATP2A3;69131 MRPL15;32210 p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011 0 -The @VARIANT$ (p.R77C) variant in @GENE$ and @VARIANT$ (p.I80Gfs*13) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2. 6637284 S100A3;2223 S100A13;7523 c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284 1 -In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519 P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 PAX3;22494 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ FLNB and p.Y437F @GENE$ (figure 3D). FLNB and OFD1 variants in individuals with AIS. (A) Pedigree of AIS twins. Case 98-73 (proband) is indicated with an arrow. (B) Protein sequences around @GENE$. p.R2003 in 11 species. (C) Local view of in silico structure analysis of the WT and mutant FLNB structures (variant H2003). The WT structure of FLNB is shown in purple, and the mutant structure of FLNB is shown in green. The side chains of R/H2003 are shown as sticks, and the other residues are shown as lines. (D) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R2003H) vector plasmids and myc-tagged WT or mutant OFD1 (@VARIANT$). 7279190 OFD1;2677 FLNB;37480 p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226 p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481 0 -"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 DVL3;20928 SCRIB;44228 p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 0 -Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and @GENE$, respectively. 5953556 CYP1B1;68035 TEK;397 G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 0 -Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), RYR1 (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (rs144901249) genes. 6180278 COL6A3;37917 DES;56469 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685 0 -Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and @VARIANT$ in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in MYO7A. 3949687 MYO7A;219 PCDH15;23401 c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 - Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and @GENE$ mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel FAT4 missense variant c.10147G>A). 5887939 CELSR1;7665 SCRIB;44228 c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818 c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060 0 -Five subjects (R279, R410, R465, R469 and R470) carried pathogenic and deleterious variants in genes known to affect glycogen metabolism (GBE1, PYGM), FAO (@GENE$ and CPT2), fatty acid and amino acid catabolism (PCCB), oxidative phosphorylation (ELAC2, NDUFA6, NDUFA10 and NUBPL), mitochondrial matrix enzymes (OAT and TIMM50). Two subjects (R302 and R462) had variants in genes involved in Ca 2+ regulation (@GENE$ and CACNA1S), glycogen metabolism (GBE1 and PHKA1) and oxidative phosphorylation (NDUFS8). Mutations in PHKA1 cause Glycogen Storage Disease type IX, X-linked phosphorylase kinase (PHK) enzyme deficiency, characterized by high muscle glycogen content and severe reduction of muscle PHK activity. However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and NDUFS8 @VARIANT$ variants remain unknown. 6072915 ACADVL;5 RYR1;68069 L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635 I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290 0 -We report digenic variants in @GENE$ and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 SCRIB;44228 CELSR1;7665 c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). 3842385 EDA;1896 WNT10A;22525 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in ZFPM2 (c.A2107C, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3). 5765430 NR5A1;3638 SRD5A2;37292 p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681 c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6. 6610752 LQT6;71688 LQT2;201 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). 5887939 PRICKLE4;22752 DVL3;20928 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903 0 -Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of @GENE$. Direct sequence analysis showing the 497A>G (@VARIANT$) mutation (d) and WT allele (e) of @GENE$. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3. 2737700 GJB2;2975 GJB3;7338 299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -These results suggest an important role of @GENE$ as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin @VARIANT$, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated @GENE$ triggered by ephrin-B2 stimulation. 7067772 ephrin-B2;3019 pendrin;20132 L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3). 3888818 KAL1;55445 TACR3;824 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$). 3888818 NELF;10648 TACR3;824 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Under the assumption of an autosomal recessive inheritance pattern, two variants were identified in @GENE$ (c.326_327insT, p.(Lys111Glnfs*27) and c.7117C>T, @VARIANT$) (Table 1, S3 Fig.). Segregation analysis showed that they were both present on the maternal allele (Figs. 1C-D). By analyzing for the presence of variants in genes implicated in intellectual disability, hearing impairment and inherited retinal disease, a heterozygous stop mutation in @GENE$ (@VARIANT$, p.(Ser512*)), a gene previously shown to be involved in autosomal recessive RP. 5967407 RP1L1;105870 C2orf71;19792 p.(Gln2373*);tmVar:p|SUB|Q|2373|*;HGVS:p.Q2373*;VariantGroup:4;CorrespondingGene:94137 c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678 1 -Four potential pathogenic variants, including @GENE$ @VARIANT$ (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), @GENE$ @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited @GENE$ T168fsX191 and @GENE$/TACI @VARIANT$ mutations are shown. 5671988 TCF3;2408 TNFRSF13B;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -Another candidate variant in @GENE$ (rs7807826) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. 6081235 MYH13;55780 NOS2;55473 c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122 p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126 0 -Some patients exhibited olfactory dysosmia and obesity, which was consistent with the clinical manifestations of extreme obesity in patients with @GENE$ variants reported in previous studies. Two novel variants of the @GENE$ gene were found in patients with anosmia, obvious small phallus, and low levels of sex hormones. c.223 - 4C > A might affect the normal splicing of exons in the PROK2 gene, and the novel variant @VARIANT$ (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the PROKR2 gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (@VARIANT$) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. 8796337 PROKR2;16368 PROK2;9268 c.306G > C;tmVar:c|SUB|G|306|C;HGVS:c.306G>C;VariantGroup:27;CorrespondingGene:60675 p. Arg164Gln;tmVar:p|SUB|R|164|Q;HGVS:p.R164Q;VariantGroup:3;CorrespondingGene:128674;RS#:751875578;CA#:311167332 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 TYRO3;4585 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (c.1514G>A, p.G505D). A novel missense mutation was found in @GENE$ (c.398G>A, @VARIANT$). 6098846 TG;2430 DUOXA2;57037 c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753 p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341 1 -Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. 5953556 TEK;397 CYP1B1;68035 p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 1 -We also identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a @VARIANT$ of @GENE$ (Table 3). 5765430 SRD5A2;37292 NR5A1;3638 c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442 single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516 1 -DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in @GENE$, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both SEC23A and @GENE$, consistent with an autosomal-recessive mode of inheritance. 4853519 SEC23A;4642 MAN1B1;5230 1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 DCTN1;3011 TARDBP;7221 p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112 p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583 0 -@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-@VARIANT$, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNQ1;85014 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ p.P642R, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, @VARIANT$ and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3). 5966321 PTK7;43672 SCRIB;44228 p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 0 -In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (c.965delA), SNAI2 (@VARIANT$) and @GENE$ (@VARIANT$) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family. 7877624 C2orf74;49849 SNAI2;31127 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 0 -One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 FZD;8321;8323 FAT4;14377 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 MITF;4892 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in @GENE$, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both SEC23A and MAN1B1, consistent with an autosomal-recessive mode of inheritance. We also identified heterozygous mutation in @GENE$ in an unaffected sibling of tall stature and normal intelligence. 4853519 MAN1B1;5230 SEC23A;4642 1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$). 3888818 NELF;10648 TACR3;824 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137 0 -Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with SETX p.I2547T and SETX p.T14I). 4293318 TARDBP;7221 TAF15;131088 p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390 p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3). 5966321 SCRIB;44228 CELSR1;7665 p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256 p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676 0 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 FGFR1;69065 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481 0 -Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), @GENE$ @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). 8739608 LAMA2;37306 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and @VARIANT$ (R284C) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation. His mother, a 40-year-old female with one pathogenic variant each in @GENE$ and @GENE$ shows unspecified myopathy with elevated creatine phosphokinase (CPK). 6292381 ANO5;100071 COL6A2;1392 p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516 c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431 0 -Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. 3125325 USH2A;66151 CDH23;11142 p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 0 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). 3888818 NELF;10648 TACR3;824 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 GNA14;68386 CAPN11;21392 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 MITF;4892 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a). 2737700 GJB2;2975 GJB3;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -PKD1 sequencing identified a likely pathogenic variant, p.(@VARIANT$), absent in parents, and a second maternally inherited variant, p.(@VARIANT$). This is extremely rare (never reported before, absent in GnomAD), but with benign computational predictions, and it was classified as hypomorphic. We cannot formally test if variants in these two patients are in trans, but we presume they contributed to the severe clinical expression. In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). 7224062 PKD1;250 PKD2;20104 Asn2167Asp;tmVar:p|SUB|N|2167|D;HGVS:p.N2167D;VariantGroup:33;CorrespondingGene:5310 Ala561Val;tmVar:p|SUB|A|561|V;HGVS:p.A561V;VariantGroup:10;CorrespondingGene:5311;RS#:542353495 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation. 6610752 LQT6;71688 KCNH2;201 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. 6707335 SPG11;41614 FUS;2521 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; @VARIANT$) and @GENE$ (@VARIANT$). 3125325 USH1G;56113 USH2A;66151 p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 1 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3). 3888818 KAL1;55445 NELF;10648 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). 5887939 CELSR1;7665 SCRIB;44228 c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 - A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. 6707335 ALS2;23264 MATR3;7830 R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$). 3888818 NELF;10648 TACR3;824 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -(A) Segregation of the @GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-@VARIANT$, and @GENE$-@VARIANT$ variants in the long-QT syndrome (LQTS) family members. 5578023 KCNQ1;85014 KCNE1;3753 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees. 6081235 HS1BP3;10980 MYOD1;7857 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 @VARIANT$, rs761703397), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS. 8621929 LRP6;1747 WNT10A;22525 c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 DVL3;20928 SCRIB;44228 p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 0 -Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ @GENE$ proteins, respectively (figure 2D, E). 7279190 TTC26;11786 FLNB;37480 p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989 p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280 1 -Novel Missense Mutation in the @GENE$ Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association? Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.@VARIANT$ p.K953E) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R). 3975370 NOD2;11156 IL10RA;1196 2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$). 3888818 KAL1;55445 TACR3;824 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-@GENE$. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. 5953556 TEK;397 CYP1B1;68035 G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and @GENE$ (ANK1) identified in SH 94-208). 4998745 USH2A;66151 Ankyrin 1;55427 p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964 C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 TYRO3;4585 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare glycine decarboxylase (@GENE$) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (@VARIANT$; p.Val2517Met) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (CELSR1) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3). 5887939 MTHFR;4349 GLDC;141 c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990 c.7549G>A;tmVar:c|SUB|G|7549|A;HGVS:c.7549G>A;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383 0 -Six variants in PKD1 occurred de-novo, three of which were not previously described: @VARIANT$.(Asp1079Alafs*25), c.8860G>T p.(Glu2954*), and c.9201+1G>A. One de-novo and novel variant was also detected in PKD2: c.992G>A p.(@VARIANT$). Types of 158 distinct possible pathogenic variants detected in @GENE$ and @GENE$ genes. 7224062 PKD1;250 PKD2;20104 c.3236del p;tmVar:c|DEL|3236|P;HGVS:c.3236delP;VariantGroup:47;CorrespondingGene:5310 Cys331Tyr;tmVar:p|SUB|C|331|Y;HGVS:p.C331Y;VariantGroup:1;CorrespondingGene:23193;RS#:144118755 0 -We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. 5966321 PTK7;43672 SCRIB;44228 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b). 7067772 EPHA2;20929 SLC26A4;20132 c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329 c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172 0 -This analysis indicated that the @GENE$ variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (rs144901249), which results in a @VARIANT$ change, are both predicted to be damaging. 6180278 CAPN3;52 DES;56469 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 p.Thr219Ile;tmVar:p|SUB|T|219|I;HGVS:p.T219I;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118 0 -The heterozygous SCN5A@VARIANT$ was carried by her father and sister but not carried by I:2. II:1 carried with @GENE$ @VARIANT$ as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index. Conclusions The digenic heterozygous KCNH2 and @GENE$ mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction. 8739608 KCNH2;201 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the @GENE$/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. 5671988 TNFRSF13B;49320 TCF3;2408 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a @GENE$ (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus. 5505202 WDR11;41229 EMX1;55799 p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418 c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694 0 - A new pathogenic variant in @GENE$ affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, was identified in patient #3. 6567512 BBS2;12122 BBS7;12395 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 0 -Mutations in @GENE$ (MITF), coding for a basic helix-loop-helix (BHLH) leucine zipper protein, are known to cause the WS2 phenotype due to defects in survival, proliferation, and migration of melanocytes. The deletion mutation (@VARIANT$) identified in this study lies in the BHLH domain and predicted to cause frameshift (p.Asn322fs) and stop codon seven amino acids downstream (Asn322Metfs*7). The missense variant (c.101T>G) in the C2orf74 gene changes the conserved amino acid Valine to Glycine (@VARIANT$). C2orf74 is an uncharacterized gene and no functional data is available, however, Expression Atlas detected the expression of the gene in the eye (https://www.ebi.ac.uk/gxa/home). The gene @GENE$ is present in the genomic region shared by all affected individuals and therefore, we consider this as a candidate gene for WS2 phenotype. 7877624 melanocyte inducing transcription factor;4892 C2orf74;49849 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 0 -According to earlier studies, @GENE$ variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. 6707335 KIF5A;55861 SPG11;41614 E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 0 -The presence of concomitant mutations, such as the TCF3 @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family. 5671988 TNFRSF13B;49320 TCF3;2408 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction. 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys." 3842385 EDA;1896 WNT10A;22525 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 CELSR1;7665 FZD6;2617 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776 0 -We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric Cx26/Cx31 connexons. Furthermore, by cotransfection of mCherry-tagged @GENE$ and GFP-tagged Cx31 in human embryonic kidney-293 cells, we demonstrated that the two connexins were able to co-assemble in vitro in the same junction plaque. 2737700 GJB6;4936 Cx26;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). 8172206 PDGFRB;1960 SLC20A2;68531 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and @GENE$ were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2). 3125325 USH2A;66151 MYO7A;219 p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798 c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 0 -However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out. 8152424 CCDC88C;18903 FGFR1;69065 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192 0 -In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (@VARIANT$), SNAI2 (c.607C>T) and C2orf74 (@VARIANT$) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family. 7877624 MITF;4892 SNAI2;31127 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. 3125325 MYO7A;219 USH2A;66151 c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); @GENE$ M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001. 4853519 SEC23A;4642 GAPDH;107053 M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with @GENE$/@GENE$ mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R. 3888818 NELF;10648 KAL1;55445 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778 0 -a, b Immunoprecipitation of EphA2 with mutated @GENE$. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by ephrin-B2 stimulation. 7067772 pendrin;20132 EphA2;20929 A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: @VARIANT$ and p.(H395N); @GENE$: @VARIANT$). 6338360 FOXC2;21091 PITX2;55454 p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GENE$ p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and @VARIANT$ was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3). 5966321 DVL3;20928 CELSR1;7665 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 0 -Therefore, this amino acid replacement may affect protein interactions taking place in the transcriptional inhibitory domain where it is located, leading to increased @GENE$ activity. In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, FOXC2 variants p.S36S (synonymous) and @VARIANT$ (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-@GENE$ genes. 6338360 PITX2;55454 AS1;736 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394 0 -Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN1;21005 NRXN2;86984 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 0 -It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, @VARIANT$, p.S82T, p. A85P, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed. 5611365 FOXC1;20373 PITX2;55454 p.P79T;tmVar:p|SUB|P|79|T;HGVS:p.P79T;VariantGroup:108;CorrespondingGene:6012 p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636 0 -Moreover, the existence of incomplete penetrance, variable expressivity and of a relatively high proportion (close to 20%) of PCG patients with rare heterozygous @GENE$ variants also suggest non-Mendelian PCG transmission in some cases. In these patients, disease outcome might depend on modifier factors (genetic, stochastic and/or environmental), as will be discussed later. Functional impact of the rare variants The two missense FOXC2 variants (@VARIANT$ and (p.(C498R)) and one of the @GENE$ amino acid substitutions (p.(P179T)) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation. The functional impact of the second PITX2 amino acid substitution, p.(A188T), could not be functionally evaluated due to DNA cloning difficulties. In fact, the two FOXC2 amino acid changes were found to be hypomorphic whereas the PITX2 amino acid substitution (@VARIANT$) behaved experimentally as a hypermorphic variant. 6338360 CYP1B1;68035 PITX2;55454 p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 TEK;397 CYP1B1;68035 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/@GENE$ signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3). 6161649 TIMP3;36322 VEGFR2;55639 c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745 c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293 0 -In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD. Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G @VARIANT$) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature. 3975370 IL10RA;1196 IL10RB;523 2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 p. S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). 2737700 GJB2;2975 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -In addition, we have confirmed that immunoreactive signal corresponding to the anti-ephrin-B2 antibody was colocalized with that to the anti-@GENE$ antibody in the inner ear (Supplementary Fig. 3g). These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of @GENE$ are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, @VARIANT$ were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. 7067772 EphA2;20929 pendrin;20132 G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Patient 3 was found to harbor a previously reported p.Arg84His variant in @GENE$, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, @VARIANT$:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3). 5765430 NR5A1;3638 ZFPM2;8008 c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963 rs9332964;tmVar:rs9332964;VariantGroup:0;CorrespondingGene:6716;RS#:9332964 0 -Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation @VARIANT$ in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes. 6565573 COL4A4;20071 COL4A3;68033 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174 0 -Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. @GENE$ gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). 8739608 KCNH2;201 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$). 8152424 FGFR1;69065 DCC;21081 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192 0 -Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 CAPN11;21392 SPTBN4;11879 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). 8152424 CDON;22996 DCC;21081 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 PROK2;9268 p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071 p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675 0 -We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in BBS6, leading to the change p.(Cys412Phe). 6567512 BBS2;12122 BBS7;12395 c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582 c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). 2737700 GJB6;4936 GJB3;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -A single @GENE$ mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. 5868303 SQSTM1;31202 TIA1;20692 p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; @VARIANT$, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (WNT10A c.637G>A, @VARIANT$) in EAS. 8621929 WNT10A;22525 LRP6;1747 g.146466A>G;tmVar:g|SUB|A|146466|G;HGVS:g.146466A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216 0 -The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. 3842385 WNT10A;22525 EDA;1896 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). 5887939 DVL3;20928 SCRIB;44228 c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 0 - Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). 8621929 LRP6;1747 WNT10A;22525 g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 1 -Finally, as regards the USH3 patients, biallelic mutations in USH2A and monoallelic mutations in @GENE$ or @GENE$ were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. 3125325 VLGR1;19815 WHRN;18739 p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795 p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (@GENE$ c.8282C>T and @GENE$ @VARIANT$). 5887939 CELSR1;7665 SCRIB;44228 c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. 6081235 HS1BP3;10980 GNA14;68386 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 1 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. 6707335 SPG11;41614 UBQLN2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 0 -Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 SCRIB;44228 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676 0 -RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 1 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, @VARIANT$ (c.100C>T) (rs121908073), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1). 4998745 GJB2;2975 TMC1;23670 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R34X;tmVar:p|SUB|R|34|X;HGVS:p.R34X;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. 6707335 SPG11;41614 ubiquilin-2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 - Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; @VARIANT$, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS. 8621929 WNT10A;22525 LRP6;1747 g.124339A>G;tmVar:g|SUB|A|124339|G;HGVS:g.124339A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 0 -Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense @GENE$ variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position. 5101836 PTPN11;2122 SOS1;4117 c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134 p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660 1 -None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis. We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: 179264731T/C, rs10277; Ch5: 179264915G/T, @VARIANT$ ]. 5868303 TIA1;20692 SQSTM1;31202 c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 rs1065154;tmVar:rs1065154;VariantGroup:2;CorrespondingGene:8878;RS#:1065154 0 -The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. 6707335 ALS2;23264 MATR3;7830 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 0 -On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 PROKR2;16368 DUSP6;55621 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482 0 -We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 GJB3;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 TEK;397 CYP1B1;68035 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, rs147680216) in EAS. The novel LRP6 c.503T>G mutation substitutes the hydrophobic methionine168 for an arginine (p.Met168Arg) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1. The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and @VARIANT$ (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance." 8621929 LRP6;1747 WNT10A;22525 c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. @GENE$ @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 TYRO3;4585 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208). 4998745 USH2A;66151 ANK1;55427 p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964 R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Sequence alterations were detected in the @GENE$ (rs144651558), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and DES (@VARIANT$) genes. 6180278 COL6A3;37917 RYR1;68069 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 0 -To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). 7067772 pendrin;20132 EphA2;20929 L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys." 3842385 EDA;1896 WNT10A;22525 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) 0 -The side chains of R/L566 and @VARIANT$ are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C). 7279190 FLNB;37480 TTC26;11786 A/T2282;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246 p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260 0 -Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (@VARIANT$)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (@VARIANT$) exhibit perturbed interaction. 5953556 TEK;397 CYP1B1;68035 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 0 -RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 1 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN2;86984 NRXN1;21005 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. 3842385 WNT10A;22525 EDA;1896 G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). 3842385 EDA;1896 WNT10A;22525 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, @VARIANT$ and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of @GENE$ (Supplemental Material, Fig. S3). 5966321 SCRIB;44228 PTK7;43672 p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 0 -The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, DCC, PROP1, PLXNA1, and @GENE$ genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 SEMA7A;2678 PROKR2;16368 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482 0 - The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane. 7067772 EphA2;20929 pendrin;20132 L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 0 - Molecular Data All three probands carry two heterozygous variants: @GENE$, @VARIANT$ (p.Pro392Leu), and @GENE$, c.1070A>G (@VARIANT$). 5868303 SQSTM1;31202 TIA1;20692 c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 1 -Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including @GENE$ may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, LRP5, @GENE$, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well. 7877624 LEF-1;7813 LRP6;1747 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 DCTN1;3011 TARDBP;7221 p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 0 -A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, @VARIANT$, was identified in patient #3. BBS1, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of @GENE$ and @GENE$ lie in this portion. 6567512 BBS2;12122 BBS7;12395 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212 0 -"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys." 3842385 WNT10A;22525 EDA;1896 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of @GENE$ (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) . 5587079 DUOX1 and -2;53905;50506 DUOX1;68136 c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 0 - Finally, a subject with the heterozygous p.R143W mutation in GJB2 (SH60-136) carried a p.D771N variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES. However, neither @VARIANT$ in @GENE$ nor @VARIANT$ in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3). 4998745 WFS1;4380 GJB2;2975 p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234 p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681 0 -The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI @VARIANT$ mutations. Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. 5671988 TNFRSF13B;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 - In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in @GENE$ (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating @GENE$ signalling. In addition to Smad1-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (p.Glu631Ter), in EGFR (table 1). Oncogenic EGFR stimulates angiogenesis via the VEGF pathway. As a truncated germline EGFR variant has not been reported in humans, c.1891G>T (@VARIANT$) in patient AVM312 was classified as likely pathogenic and EGFR as a candidate gene due to the vital role of EGFR in EGF and VEGF signalling. 6161649 ZFYVE16;8826 BMP;55955 p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765 p.Glu631Ter;tmVar:p|SUB|E|631|X;HGVS:p.E631X;VariantGroup:8;RS#:909905659 0 - Tumor analysis MMR deficiency in tumor samples was assessed by microsatellite instability analysis and immunohistochemical detection of the four MMR proteins (MLH1, MSH2, MSH6, and @GENE$). 11 @GENE$ codon 12/13 mutations were screened with Sanger sequencing. 12 Functional MMR assay In vitro MMR activity assay was performed as previously described. 13 RESULTS We performed germline whole-exome sequencing on three CRC patients diagnosed before 60 years of age (III-1, III-7, III-8, Figure 1A) and who belonged to a CRC family comprising of seven cancer patients divided over two generations. Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: c.3299C > T, @VARIANT$) and MUTYH (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition. 7689793 PMS2;133560 KRAS;37990 p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473 p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475 0 -Four genes (including AGXT2, @GENE$, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies. 5725008 ZFHX3;21366 SCAP;8160 p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 -In this family, the patient (II: 1) with digenic heterozygous mutations of KCNH2 p.307_308del and @GENE$ @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without @GENE$ @VARIANT$ showed normal QT intervals and cardiac function. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees. 6081235 VPS13C;41188 MRPL15;32210 c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211 c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 0 -25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25 The contribution of the genetic variants, other than @GENE$ and @GENE$, to cancer risk cannot be completely excluded. 7689793 MSH6;149 MUTYH;8156 c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919 p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 0 -One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$). 5887939 CELSR2;1078 FAT4;14377 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329 0 -The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and HNF4A @VARIANT$. Both mutations are novel and whilst a different mutation, R80W, has been reported in @GENE$, further evidence to support the pathogenicity of E508K is lacking. 4090307 HNF1A;459 HNF4A;395 E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173 R80Q;tmVar:p|SUB|R|80|Q;HGVS:p.R80Q;VariantGroup:2;CorrespondingGene:3172 0 -The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 0 -"Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser." 3842385 WNT10A;22525 EDA;1896 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 0 -Proband 17 inherited @GENE$ p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out. Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants. 8152424 CHD7;19067 FGFR1;69065 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482 0 -The creation of the downstream acceptor splice site results in 3 bp deletion (@VARIANT$). A heterozygous 3 bp deletion is clearly visible in the sequencing data derived from P3, but not in C1. G, The 3 bp deletion causes the deletion of p.Gly74. The deleted nucleotides are enclosed in the red box. H, A multiple alignment analysis shows that p.Gly74 is conserved among Eukaryotic species ACADS and ECHDC1 deficiencies act in synergy on cellular EMA excretion Having shown that 3/82 SCADD individuals with common ACADS variants were heterozygous for loss-of-function ECHDC1 variants, we speculated that ECHDC1 haploinsufficiency, in combination with the common @GENE$ @VARIANT$ variant, had an additive effect on EMA levels. To further examine this hypothesis, we measured EMA levels in cultured fibroblasts from healthy individuals, who were either wild-type, heterozygous or homozygous for ACADS c.625G>A, with or without approximately halved knockdown of ECHDC1 mRNA levels (Figure 5). The six cell lines were constructed by transduction either with non-targeting shRNA or with @GENE$ targeting shRNA. 8518634 ACADS;20057 ECHDC1;23106 c.221_223del;tmVar:c|DEL|221_223|;HGVS:c.221_223del;VariantGroup:10;CorrespondingGene:55862 c.625G>A;tmVar:c|SUB|G|625|A;HGVS:c.625G>A;VariantGroup:1;CorrespondingGene:35;RS#:1799958;CA#:145599 0 -myc-pendrin A372V, L445W, @VARIANT$, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected. f Relative amount of cell surface pendrin is shown. Mean +- SEM; one-way ANOVA; **p < 0.01; *p < 0.05; (n = 3). Source data are provided as a Source Data file. Several amino-acid substitutions of @GENE$ have been identified from Pendred syndrome patients as well as non-syndromic hearing loss patients with EVA. 7067772 EphA2;20929 pendrin;20132 Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys." 3842385 EDA;1896 WNT10A;22525 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 0 -Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 HS1BP3;10980 UNC13B;31376 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d). 2737700 Cx31;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of @GENE$ @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (KRAS @VARIANT$) was absent in this tumor, which points toward retained @GENE$ repair activity. 7689793 MSH6;149 MUTYH;8156 p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473 c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137 0 -There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes. 6565573 COL4A5;133559 COL4A3;68033 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286 0 -KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, @GENE$-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNE1;3753 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. 3842385 WNT10A;22525 EDA;1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -The loss-of-function variation in @GENE$ or @GENE$ (e.g., CACNA1C-Q1916R), which produces inadequate inward hybrid currents, is responsible for the pathopoiesis of ERS. Thus, from the mechanistic point of view, INa and ICa-L show a synergistic effect on the repolarization as two ingredients of the inward currents. In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental CACNA1C-@VARIANT$ mutation might be partly compensated by the persistent inward tail INa produced by the SCN5A-@VARIANT$ channel. 5426766 SCN5A;22738 CACNA1C;55484 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 1 -Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). 8739608 LAMA2;37306 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099 0 -Nonetheless, recent studies proved that @GENE$ variants have a role in ALS. According to earlier studies, KIF5A variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. 6707335 KIF5A;55861 SPG11;41614 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and TAF15 @VARIANT$ with @GENE$ p.I2547T and SETX p.T14I). 4293318 VAPB;36163 SETX;41003 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. 5953556 TEK;397 CYP1B1;68035 p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation. 6610752 KCNH2;201 LQT6;71688 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -M2, CYP1B1: @VARIANT$. M3, @GENE$: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases. 6338360 CYP1B1;68035 PITX2;55454 p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 0 -We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe). 6567512 BBS2;12122 BBS6;10318 c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 0 -Two variants, likely pathogenic @VARIANT$ and pathogenic @VARIANT$, in HMBS were found in two subjects. Pathogenic variants in HMBS are associated with Acute Intermittent Porphyria. We consider HMBS variants as incidental findings that are likely unrelated to phenotype. Variant segregation in subjects All subjects were heterozygous carriers of pathogenic or deleterious variants in genes known to affect various enzymatic pathways of cellular energy. Five subjects (R279, R410, R465, R469 and R470) carried pathogenic and deleterious variants in genes known to affect glycogen metabolism (GBE1, PYGM), FAO (ACADVL and CPT2), fatty acid and amino acid catabolism (PCCB), oxidative phosphorylation (ELAC2, NDUFA6, NDUFA10 and @GENE$), mitochondrial matrix enzymes (OAT and TIMM50). Two subjects (R302 and R462) had variants in genes involved in Ca 2+ regulation (RYR1 and CACNA1S), glycogen metabolism (GBE1 and @GENE$) and oxidative phosphorylation (NDUFS8). 6072915 NUBPL;11854 PHKA1;1981 p. R175W;tmVar:p|SUB|R|175|W;HGVS:p.R175W;VariantGroup:4;CorrespondingGene:5256;RS#:376233279;CA#:10361894 p. R225Q;tmVar:p|SUB|R|225|Q;HGVS:p.R225Q;VariantGroup:11;CorrespondingGene:779 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 MITF;4892 TYRO3;4585 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and @GENE$-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers. 5578023 KCNQ1;85014 KCNE1;3753 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. 6081235 CACNA1A;56383 REEP4;11888 p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346 p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 - CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2). DISCUSSION In this study, we performed exome sequencing on 584 patients with @GENE$ and without a molecular diagnosis. Variants in seven @GENE$-mediated genes involved in somitogenesis were selected for analysis. 7549550 CS;56073 TBX6;3389 c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129 p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 Cx31;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes. 6565573 COL4A3;68033 COL4A4;20071 Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286 1 -The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 - Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). 8621929 LRP6;1747 WNT10A;22525 p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 1 -To further analyze the role of @GENE$ in Pendred syndrome, direct sequencing of the EPHA2 gene in 40 Japanese hearing loss patients with EVA carrying mono-allelic mutation of SLC26A4 were examined. While mutation of ~70 genes causing hearing loss were previously identified as a human nonsyndromic deafness gene, they were not identified in these patients. On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b). These EPHA2 mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of @GENE$ was previously reported. 7067772 EphA2;20929 SLC26A4;20132 p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772 0 -Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 KAL1;55445 PROKR2;16368 p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 ->G (p.Asn692Ser) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (@VARIANT$) was identified in @GENE$ (table 1). 6161649 CDH2;20424 IL17RD;9717 c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588 p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 SNAI2;31127 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -For example, two variants in proband P15, @VARIANT$ in PROKR2 and p. Tyr503His in @GENE$ (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother. 8152424 DDB1 and CUL4 associated factor 17;80067;1642 DMXL2;41022 p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381 p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe). 6567512 BBS1;11641 BBS7;12395 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212 0 -In the individual carrying the @VARIANT$ @GENE$ variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. 6707335 NEFH;40755 GRN;1577 P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372 C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519 1 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo. In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. 6161649 MAP4K4;7442 CDH2;20424 p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730 0 -"The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes. ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of @GENE$ were detected." 3842385 EDA;1896 WNT10A;22525 Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -@GENE$ gene might interact with @GENE$ gene product and give rise to the spectrum of phenotype varying from severe phenotype with complete penetrance to partial features. Conclusion In this study, we analysed a large family segregating Waardenburg syndrome type 2 to identify the underlying genetic defects. Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the MITF gene and a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the C2orf74 was identified. 7877624 C2orf74;49849 MITF;4892 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 1 -Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2). 3125325 USH1G;56113 MYO7A;219 p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 0 -Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and c.353A > G (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). 7463850 EHMT1;11698 MFSD8;115814 c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857 c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -For a more comprehensive review of the role of GATA4 in CHD we refer to Ref.. By contrast, the few @GENE$ missense mutations found in 46,XY DSD individuals with or without CHD are all located in the N-terminal zinc finger domain, which is responsible for DNA binding and interaction with cofactors. Functional characterization of GATA4 variants with respect to the 46,XY DSD phenotype has only been performed for the p.Gly221Arg mutation so far. In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor FOG2. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the @GENE$ promoter for GATA4 variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only @VARIANT$ and @VARIANT$ are close to Zn binding sites. 5893726 GATA4;1551 CYP17;73875 Gly221;tmVar:p|Allele|G|221;VariantGroup:4;RS#:398122402(Expired) Cys238;tmVar:p|Allele|C|238;VariantGroup:0;CorrespondingGene:2626 0 -RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -One missense mutation (@VARIANT$) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female @GENE$-Q1916R mutation carriers, which led to the incomplete penetrance. 5426766 SCN5A;22738 CACNA1C;55484 p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 1 -Six variants in @GENE$ occurred de-novo, three of which were not previously described: @VARIANT$.(Asp1079Alafs*25), c.8860G>T p.(Glu2954*), and c.9201+1G>A. One de-novo and novel variant was also detected in @GENE$: c.992G>A p.(@VARIANT$). 7224062 PKD1;250 PKD2;20104 c.3236del p;tmVar:c|DEL|3236|P;HGVS:c.3236delP;VariantGroup:47;CorrespondingGene:5310 Cys331Tyr;tmVar:p|SUB|C|331|Y;HGVS:p.C331Y;VariantGroup:1;CorrespondingGene:23193;RS#:144118755 0 -The p.(@VARIANT$) mutation was predicted to be highly destabilizing. (C) Alignment of P4B3 domain (a.a. 1059-1097 of human @GENE$). While @VARIANT$ is highly conserved among orthologs of LRP6 and @GENE$, zebrafish LRP5 and Drosophila Arrow use threonine and aspartate, respectively, at this position. 8621929 LRP6;1747 LRP5;1746 Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 Asparagine1075;tmVar:p|Allele|N|1075;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$). 5887939 CELSR1;7665 PTK7;43672 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 SNAI3;8500 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 MITF;4892 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. 6161649 SCUBE2;36383 VEGFR2;55639 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 0 -Digenic Inheritance of @GENE$ and @GENE$ Mutations in Patient with Infantile Dilated Cardiomyopathy Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in MYH7 (@VARIANT$; @VARIANT$). 6359299 LAMA4;37604 MYH7;68044 c.2770G > A;tmVar:c|SUB|G|2770|A;HGVS:c.2770G>A;VariantGroup:0;CorrespondingGene:3910;RS#:121913628;CA#:13034 p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034 0 -Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). 3125325 CDH23;11142 USH1G;56113 p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798 p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. 6707335 ALS2;23264 MATR3;7830 R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 0 -Mice lacking @GENE$ develop cardiomyopathy and have an increased frequency of sudden death upon stress; electron microscopy of these mice revealed malformed blood vessels and micro-circulation abnormalities. Moreover, patients carrying a LAMA4 Pro943Leu mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. 6359299 LAMA4;37604 MYH7;68044 L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954 R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212 0 -This is in line with the data from previous studies; according to which, @GENE$ is a causative gene of ALS-FTD. The NEK1 @VARIANT$ variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. 6707335 TBK1;22742 CCNF;1335 R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 0 -Our results indicate that the novel @GENE$-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers. 5578023 KCNH2;201 KCNE1;3753 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 MITF;4892 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The ORVAL prediction revealed five disease-causing digenic combinations involving DUSP6, ANOS1, @GENE$, PLXNA1, PROP1, and @GENE$ genes (Table 3). The absence of variant combinations involving the PROKR2 gene variant @VARIANT$ excludes its implication in digenic inheritance in the index case (HH12). Furthermore, since the variant is novel and has no functional evidence of pathogenicity, it is likely to be benign. Further molecular studies are needed to prove the deleterious character of the PROKR2 Lys205del variant. Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(Val114Leu)]. 8446458 DCC;21081 SEMA7A;2678 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050 0 -Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel @VARIANT$ variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. 6707335 GRN;1577 SQSTM1;31202 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 0 -On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The DUSP6 gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 PROKR2;16368 SEMA7A;2678 c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482 0 -On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 PROKR2;16368 SEMA7A;2678 p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482 0 -On the other hand, two missense mutations of the EPHA2 gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), @GENE$: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b). 7067772 SLC26A4;20132 EPHA2;20929 c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772 c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329 1 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). 7463850 EHMT1;11698 MFSD8;115814 p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857 p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656 0 -Only three variants were homozygous in three patients: (1) @GENE$: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient. 6098846 DUOX2;9689 DUOXA2;57037 c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155 c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064 0 -Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 EDNRB;89 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (@VARIANT$), @GENE$ (@VARIANT$), and @GENE$ (rs144901249) genes. 6180278 CAPN3;52 DES;56469 rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 0 -The mother and son reported by Beijers et al. were heterozygous for @GENE$ G31D and HNF4A @VARIANT$, but the @VARIANT$ substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/). It is therefore unlikely to be causative of MODY. The proband described by Forlani et al. was heterozygous for HNF1A E508K and @GENE$ R80Q. 4090307 HNF1A;459 HNF4A;395 H214Y;tmVar:p|SUB|H|214|Y;HGVS:p.H214Y;VariantGroup:5;CorrespondingGene:3172 G31D;tmVar:p|SUB|G|31|D;HGVS:p.G31D;VariantGroup:4;CorrespondingGene:6927;RS#:137853247;CA#:124487 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The genotypes of @GENE$ (NM_001257180.2: @VARIANT$, p.His596Arg) and @GENE$ (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. 6707335 SPG11;41614 UBQLN2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -A single-nucleotide duplication (@VARIANT$/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (@VARIANT$/p.Cys520Tyr) that cosegregated with both the AI phenotype and the @GENE$ mutation. 6785452 LAMA3;18279 ENAM;9698 c.395dupA;tmVar:c|DUP|395|A|;HGVS:c.395dupA;VariantGroup:18;CorrespondingGene:13801 c.1559G>A;tmVar:c|SUB|G|1559|A;HGVS:c.1559G>A;VariantGroup:6;CorrespondingGene:3909 0 -Among the 8 novel variants, 4 were classified as P (p.C176R and @VARIANT$ in @GENE$, @VARIANT$ in @GENE$) or LP (p.D137E in DUOX2), the other were classified as VUS. 7248516 TSHR;315 DUOX2;9689 p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253 p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506 0 -We identified four genetic variants (KCNQ1-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and @GENE$-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and @GENE$-@VARIANT$, using the whole-cell patch clamp technique. 5578023 KCNE1;3753 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 0 -One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare @GENE$ missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 CELSR2;1078 FZD6;2617 c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776 c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776 0 -Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (@VARIANT$) and TNNT2 (@VARIANT$), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; @GENE$:part of the sarcomere, and @GENE$:part of the ECM/signalling component. 6359299 MYH7;68044 LAMA4;37604 Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773 Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235 0 -Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons. 2737700 Cx26;2975 Cx31;7338 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -On the other hand, EphA2 overexpression did not affect localization of @VARIANT$. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) @GENE$ (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f). 7067772 pendrin;20132 ephrin-B2;3019 G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423 L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 0 - A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, was identified in patient #3. BBS1, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of @GENE$ and @GENE$ lie in this portion. 6567512 BBS2;12122 BBS7;12395 p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, @VARIANT$) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B). 8621929 LRP6;1747 WNT10A;22525 p.Met1445Val;tmVar:p|SUB|M|1445|V;HGVS:p.M1445V;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 1 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; @VARIANT$) c.1226A>G; @VARIANT$ and @GENE$ (MIM 600509; NM_000352.4; rs151344623) c.3989-9G>A mutations. 5505202 GBA;68040 ABCC8;68048 rs7673715;tmVar:rs7673715;VariantGroup:2;RS#:7673715 p.N409S;tmVar:p|SUB|N|409|S;HGVS:p.N409S;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. 5953556 TEK;397 CYP1B1;68035 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 0 -Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, FGF10, @GENE$, RIPK4 and EYA1; and RET for PIK3R3 with @GENE$, which also is connected with RIPK4. 6726737 GLI2;12725 PTPN11;2122 c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322 p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269 0 -The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. 6707335 ALS2;23264 MATR3;7830 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 - LIMITATIONS Our study was performed only in the statistical field on @GENE$ @VARIANT$ and @GENE$ @VARIANT$ by WES and predisposing genes analyses. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 1 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ @VARIANT$, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 DVL3;20928 SCRIB;44228 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 0 - In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes @GENE$, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant c.676G>A (@VARIANT$) was identified in IL17RD (table 1). IL17RD is highly expressed in vessel endothelial cells and vascularised organs, where it inhibits fibroblast growth factor (FGF) and plays critical roles in endothelial cell proliferation and angiogenesis. In contrast to FGF inhibition, overexpression of @GENE$ attenuates the degradation of epidermal growth factor recepter (EGFR) and enhances downstream MAPK signalling (figure 3). 6161649 N-cadherin;20424 IL17RD;9717 c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730 p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588 0 -(A) The alignment of orthologs of the human @GENE$ protein. The R171 and G213 residues are represented by arrowheads. (B) The predicted 2D structure of human WNT10A protein. The @VARIANT$ and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. @VARIANT$ is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The G257 and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the EDA trimer. (B) The side view of the @GENE$ trimer. 3842385 WNT10A;22525 EDA;1896 R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555 I312;tmVar:p|Allele|I|312;VariantGroup:7;CorrespondingGene:1896 0 -Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with BSP+ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates @GENE$ missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1). 6081235 REEP4;11888 TOR2A;25260 c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211 p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 0 -Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers. 5578023 KCNQ1;85014 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 MITF;4892 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and @GENE$ p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a). 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Two potential disease-causing mutations were identified: (d) ENAM: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) LAMA3 missense mutation @VARIANT$/p.Cys520Tyr. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (@GENE$ and @GENE$) mutations. 6785452 ENAM;9698 LAMA3;18279 c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801 c.1559G>A;tmVar:c|SUB|G|1559|A;HGVS:c.1559G>A;VariantGroup:6;CorrespondingGene:3909 1 -In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (c.46C>G; p.L16V) and @GENE$ (@VARIANT$). 3125325 USH1G;56113 USH2A;66151 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382 0 -The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/@GENE$ @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. 5671988 TACI;49320 TCF3;2408 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -In this family, the evidence-based on the genetic and functional findings indicated that the loss-of-function mutation @GENE$-@VARIANT$ was the detrimental variation, and that the gain-of-function variant SCN5A-R1193Q modulated the phenotype. The candidate genes of ERS included CACNA1C and SCN5A, which suggests that the interaction of variations in these 2 genes may potentially modify the penetrance of ERS phenotypes. As previously reported, @GENE$-@VARIANT$ channels showed inactivation gating and generated a persistent, non-inactivating inward sodium current (INa), which was associated with LQTS. 5426766 CACNA1C;55484 SCN5A;22738 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 0 -Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and @VARIANT$ variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form. 6707335 GRN;1577 SIGMAR1;39965 R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 0 -To the best of our knowledge, two of the identified variants (FOXC2: @VARIANT$, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG. 6338360 FOXC2;21091 PITX2;55454 c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303 p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498 0 -The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. 3842385 EDA;1896 WNT10A;22525 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 SNAI2;31127 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -On the other hand, mis-localization of pendrin @VARIANT$ from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding. Here, we found that @GENE$ A372V, L445W, Q446R, and G672E did not bind to EphA2. Given the fact that loss of EphA2 disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with @GENE$. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation. 7067772 pendrin;20132 EphA2;20929 A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the @GENE$ repeat expansion or a missense variant in SOD1 in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$). 4293318 C9ORF72;10137 FUS;2521 p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311 p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953 0 -Although the majority of @GENE$ mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging. In the @GENE$ gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and @VARIANT$). 6707335 FUS;2521 TBK1;22742 K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110 R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683 0 -GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and @GENE$, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary @GENE$-binding site. 5953556 TEK;397 CYP1B1;68035 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -25 The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and @GENE$ (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in @GENE$ might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 7689793 EBNA1BP2;4969 CAPN9;38208 c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988 p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$). 3888818 KAL1;55445 TACR3;824 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3). 3888818 TACR3;824 NELF;10648 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I). 4293318 VAPB;36163 TAF15;131088 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127 0 -The mother and son reported by Beijers et al. were heterozygous for HNF1A G31D and @GENE$ @VARIANT$, but the G31D substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/). It is therefore unlikely to be causative of MODY. The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and HNF4A R80Q. 4090307 HNF4A;395 HNF1A;459 H214Y;tmVar:p|SUB|H|214|Y;HGVS:p.H214Y;VariantGroup:5;CorrespondingGene:3172 E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173 0 - CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. @GENE$ @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Limb Girdle Muscular Dystrophy due to Digenic Inheritance of @GENE$ and @GENE$ Mutations We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (@VARIANT$), CAPN3 (@VARIANT$), and DES (rs144901249) genes. 6180278 DES;56469 CAPN3;52 rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 0 -Statistical analysis of pro-COL1A1 colocalization with endoplasmic reticulum (ER) or trans-Golgi by confocal microscopy Genotype of cell line Manders coefficient (M2) ER (PDI) overlapping pro-@GENE$ trans-Golgi (TGN38) overlapping pro-COL1A1 Wt 0.86 (N = 19) 0.11 (N = 27) SEC23Ac.1200G>C/+ 0.79 (N = 16) 0.13 (N = 28) SEC23Ac.1200G>C/+ MAN1B1@VARIANT$/+ 0.69*** (N = 59) 0.17* (N = 150) SEC23Ac.1200G>C/c.@VARIANT$; @GENE$c.1000C>T/c.1000C>T 0.73*** (N = 41) 0.18** (N = 138) To determine whether increased intracellular levels of pro-COL1A1 were due to abnormal accumulation of this protein in the Golgi of mutant cells, double immunofluorescence confocal microscopy with antibodies against pro-COL1A1 and TGN38, an integral membrane protein in the trans-Golgi, was performed. 4853519 COL1A1;73874 MAN1B1;5230 c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197 1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384 0 -(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. 4470809 TBK1;22742 OPTN;11085 p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520 0 -Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. 6707335 ALS2;23264 MATR3;7830 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited. 6371743 MBD5;81861 NRXN1;21005 c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -Moreover, the presence of other variants (KCNQ1-p.R583H, @GENE$-@VARIANT$, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNE1;3753 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 1 -Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 GNA14;68386 UNC13B;31376 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2. 5671988 TCF3;2408 TACI;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$). 6567512 BBS1;11641 BBS6;10318 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. 2737700 GJB2;2975 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -We identified four genetic variants (@GENE$-p.R583H, KCNH2-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$) in an LQTS family. 5578023 KCNQ1;85014 KCNH2;201 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. 8739608 SCN5A;22738 KCNH2;201 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation. 6610752 LQT6;71688 KCNH2;201 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 0 -We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 GJB3;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Furthermore, @GENE$ presented 2 variants in patient 1. Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. @GENE$ for EVC, FGF10, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with RIPK4. 6726737 RIPK4;10772 GLI3;139 c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322 c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269 0 -A nonsense variant in @GENE$ (NM_000625.4: c.2059C>T, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. ATP2A3 is highly expressed in cerebellar Purkinje cells (Allen Brain Atlas) and is a member of the P-type ATPase superfamily that includes the gene (@GENE$) causally associated with rapid-onset dystonia-Parkinsonism (DYT12). GNA14 and HS1BP3 variants in pedigree with BSP+ and Parkinsonism A novel HS1BP3 nonsynonymous SNV (c.94C>A [NM_022460.3], @VARIANT$ [NP_071905.3]) was found in a father and son with severe BSP+ (Family 10043; Figure 6; Tables 1, 5, 8 and S2; Data S1). 6081235 NOS2;55473 ATP1A3;113729 p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 0 -Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 MITF;4892 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls. 2737700 GJB2;2975 Cx31;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -@GENE$ @VARIANT$ and SCN5A @VARIANT$ of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ p.R1865H. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense @GENE$ variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position. 5101836 neurofibromatosis 1;226 SOS1;4117 c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134 p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660 0 -We propose that cysteine to arginine change in position 238 of GATA4 lacks activity to bind DNA reducing the transactivation of @GENE$ critically. By contrast, variants @VARIANT$ and p@VARIANT$ found in cases 2 and 3 did not affect @GENE$ promoter activity. 5893726 AMH;68060 CYP17;73875 p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748 Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038 0 -Variant in @GENE$ (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well. No potentially pathogenic rare variant was identified. In order to identify variant(s) in other genes which might influence the expressivity of WS phenotype in our cases, exome data was filtered by using an unbiased and hypothesis-free approach. A rare missense variant (c.101T>G; @VARIANT$) in the C2orf74 gene was identified in both affected individuals. 7877624 TYRO3;4585 RNF43;37742 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (@VARIANT$; p.E2135fsX31), and six missense mutations, four of which (@VARIANT$, p.R1379P, p.D2639G, and p.R3043W) had not been previously reported. They affect amino acid residues located in the 11th, 13th and 25th cadherin repeat and the extracellular region adjacent to the transmembrane domain (3065-3085), respectively (Tables 2, 3 Figure 1). Intriguingly, the p.R1060W mutation, which affects a residue in the 10th cadherin repeat that belongs to a canonical motif (DRE) predicted to bind Ca2+ , has previously been reported in an isolated form of deafness, DFNB12 (cited in Astuto et al.). Two pathogenic or presumably pathogenic mutations in @GENE$, specifically, a nonsense mutation (p.R991X) and a novel missense mutation (p.R1273S), were found in two patients. 3125325 CDH23;11142 PCDH15;23401 c.6404_6405delAG;tmVar:c|DEL|6404_6405|AG;HGVS:c.6404_6405delAG;VariantGroup:207;CorrespondingGene:65217 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in @GENE$, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in USH2A. 3125325 MYO7A;219 USH1C;77476 c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968 c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene. 6707335 ALS2;23264 DYNC1H1;1053 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 0 -In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519 R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 PAX3;22494 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -The @GENE$ variant @VARIANT$ did not show significant protein stability differences with the wild-type protein (Fig 6C and Fig 6D). @GENE$ @VARIANT$ variant decreases protein stability. 6338360 PITX2;55454 FOXC2;21091 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 p.H395N;tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303 0 -Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes. 6180278 COL6A3;37917 DES;56469 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. 8152424 DDB1 and CUL4 associated factor 17;80067;1642 CHD7;19067 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636 0 -Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue TCF3 @VARIANT$ mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of TACI gene in the proband II.2. 5671988 TNFRSF13B;49320 TCF3;2408 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 - CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in @GENE$ and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway. 7549550 MYOD1;7857 TBX6;3389 p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491 p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682 0 -A male (ID104) was found to have a heterozygous missense variant @VARIANT$ (p.Lys330Met) in EHMT1 and a missense variant c.1777C > G (@VARIANT$) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. 7463850 SLC9A6;55971 EHMT1;11698 c.989A > T;tmVar:c|SUB|A|989|T;HGVS:c.989A>T;VariantGroup:1;CorrespondingGene:79813;RS#:764291502;CA#:5375151 p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465 0 -We found that @GENE$ variant @VARIANT$ lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and Pro226Leu activated the @GENE$ promoter similar to wt. 5893726 GATA4;1551 CYP17;73875 Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626 Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A). 5887939 SCRIB;44228 FZD1;20750 c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865 c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 SNAI2;31127 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -For Case 1, a novel missense VUS (variant of unknown significance) variant (c.361C>T; @VARIANT$) in the @GENE$ gene was identified in the patient and his father. A rare variant in @GENE$, @VARIANT$; p.Thr143Ile, was detected in Case 2 and was classified as VUS. 7696449 STAR;297 AMH;68060 p.Arg121Trp;tmVar:p|SUB|R|121|W;HGVS:p.R121W;VariantGroup:7;CorrespondingGene:6770;RS#:34908868;CA#:4715265 c.428C>T;tmVar:c|SUB|C|428|T;HGVS:c.428C>T;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862 0 -Of the 3 novel variants in @GENE$, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and @VARIANT$ and p.E389K were missense mutations located in the peroxidase-like domain (Fig. S3A). A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, DUOXA2 and @GENE$). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). 7248516 DUOX2;9689 TPO;461 p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506 p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885 0 -On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b). 7067772 EPHA2;20929 SLC26A4;20132 c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329 p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403 0 -Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel @GENE$ missense variant c.10147G>A). 5887939 CELSR1;7665 FAT4;14377 c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808 c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060 0 -Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (g.68531T>G, c.503T>G, p.Met168Arg; @VARIANT$, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (WNT10A c.637G>A, rs147680216) in EAS. 8621929 WNT10A;22525 LRP6;1747 g.112084C>G;tmVar:g|SUB|C|112084|G;HGVS:g.112084C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462 g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -We found that @GENE$-@VARIANT$ was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and @GENE$-@VARIANT$ were previously reported to produce more severe phenotypes when combined with disease-causing alleles. 5578023 KCNQ1;85014 KCNE1;3753 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Notably, the common variants @GENE$-@VARIANT$ and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers. 5578023 KCNH2;201 KCNE1;3753 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Although the majority of @GENE$ mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging. In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (@VARIANT$) were identified in our patient cohort. The patient (#90u) carrying the novel K631del deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. @GENE$ variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and @VARIANT$). 6707335 FUS;2521 CCNF;1335 K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110 R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683 0 -In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and @VARIANT$(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of KAl1 gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function. Prokineticin-2 (@GENE$) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed PROK2/@GENE$ variants, which was significantly higher than the 9% in the Caucasian population. 8796337 PROK2;9268 PROKR2;16368 c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223 c.1524del A;tmVar:c|DEL|1524|A;HGVS:c.1524delA;VariantGroup:17;CorrespondingGene:3730 0 -Moreover, gain-of-function mutation of SCN5A commonly induced LQTS, while loss-of-function mutation of @GENE$ ordinary led to sinoatrial node dysfunction, atrioventricular block, atrial fibrillation and cardiomyopathy (e.g., ARVC/D; Blana et al.,; Han et al.,). Therefore, in this study, SCN5A @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 DVL3;20928 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 0 -Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in @GENE$ (c.1175C>T, @VARIANT$) and a heterozygous variant in @GENE$ (c.1070A>G, @VARIANT$). 5868303 SQSTM1;31202 TIA1;20692 p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866 p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 1 -Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and @VARIANT$ in @GENE$ as well as F193C, S198F and @VARIANT$ in @GENE$, have been reported previously in patients with hearing impairment. 2737700 Cx26;2975 Cx32;137 A197S;tmVar:p|SUB|A|197|S;HGVS:p.A197S;VariantGroup:3;CorrespondingGene:2706;RS#:777236559 G199R;tmVar:p|SUB|G|199|R;HGVS:p.G199R;VariantGroup:17;CorrespondingGene:2705 0 -Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK @VARIANT$ and HA-@GENE$ Q214P, respectively, was significantly diminished. 5953556 CYP1B1;68035 TEK;397 A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. 6707335 GRN;1577 SQSTM1;31202 R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 0 -Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, @GENE$, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, @GENE$, and BCL9L) as well. 7877624 LRP4;17964 BCL9;3191 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. 8172206 PDGFRB;1960 SLC20A2;68531 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 0 -In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively. 2737700 GJB3;7338 GJB2;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 PAX3;22494 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited. 6371743 MBD5;81861 NRXN1;21005 p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$). 6610752 KCNH2;201 LQT6;71688 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 1 -The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. 6637284 SETDB1;32157 S100A13;7523 c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 SNAI2;31127 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 GJB6;4936 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROKR2;16368 FGFR1;69065 p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071 p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for @GENE$ , 11%-15% for @GENE$ , and for USH2A in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor. 3125325 CDH23;11142 PCDH15;23401 c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415 c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903 0 -Exome sequencing performed with DNA from Patient 3 identified 13 homozygous variants that were rare and predicted to be deleterious (Table S1 in the Supplementary Appendix), 2 of which were also homozygous in the two other affected siblings: @GENE$ (NM_207111.3) c.2251C T, @VARIANT$ and @GENE$ (NM_001102653.1) c.998G T, @VARIANT$; these variants were not identified or were heterozygous in the unaffected family members (Fig. 1). 3738065 RNF216;19442 OTUD4;35370 p.R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853 p.G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858 1 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) 0 -(B) The predicted 2D structure of human @GENE$ protein. The R171 and @VARIANT$ residues are in yellow. The 3D structure of @GENE$ is shown in Figure 4. The @VARIANT$ residue is located at the interface of two trimers. 3842385 WNT10A;22525 EDA;1896 G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216 G257;tmVar:c|Allele|G|257;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), MBD5 (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited. 6371743 GAMT;32089 NRXN1;21005 p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620 c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814 0 -(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). 8172206 SLC20A2;68531 PDGFRB;1960 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 TACR3;824 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation. 5671988 TCF3;2408 TNFRSF13B;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, @GENE$-@VARIANT$, and @GENE$-@VARIANT$ could be LQTS modifiers. 5578023 KCNH2;201 KCNE1;3753 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 1 -Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing. 8739608 SCN5A;22738 KCNH2;201 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Among the 18 variants, three missense variations, the new @GENE$ mutation (@VARIANT$) and the known IL10RA missense variants (@VARIANT$ and G351R), caught our attention: we hypothesized that these three variants might together contribute to an increased risk of developing early onset IBD. Variants in combined heterozygosis on different genes may have a cumulative effect and contribute to the disease phenotype, probably due to the dysregulation of different pathways. Digenic contribution to multigenic diseases is poorly investigated by GWAS studies. However, recent data showed that digenic or multigenic inheritance might be underrated mechanisms explaining familial recurrence of multifactorial diseases. IL10RA (11q23) and @GENE$ (21q22) are attractive inflammatory bowel disease candidate genes: they encode for the alpha and beta chain, respectively, that form a tetrameric cell bound structure able to bind interleukin (IL-10). 3975370 NOD2;11156 IL10RB;523 K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561 0 -Mutations in @GENE$ and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. 6371743 NRXN1;21005 NRXN2;86984 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -(c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type @GENE$ (Table 3), KCNH2 @VARIANT$ showed a decreasing trend in molecular weight and increasing instability. However, the prediction of theoretical pI, aliphatic index and GRAVY presented no significant differences. Compared to the Nav1.5 protein properties of wild-type @GENE$, SCN5A p.R1865H slightly increased its molecular weight and aliphatic index but reduced its instability index. 8739608 KCNH2;201 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -These two individuals were heterozygous carriers of p.R1141X mutation in ABCC6 and @VARIANT$ in @GENE$. Since heterozygous carriers of @VARIANT$ in @GENE$ alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. 2900916 GGCX;639 ABCC6;55559 p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. 5953556 CYP1B1;68035 TEK;397 p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B). 3842385 WNT10A;22525 EDA;1896 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326 0 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN2;86984 NRXN1;21005 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -R583H mutant channels were investigated by analyzing ionic currents from cells expressing the wild-type (WT) channel (@GENE$-WT) or KCNQ1-p.R583H and from cells co-expressing the KCNQ1 and KCNE1 subunits (KCNQ1-WT+KCNE1 or KCNQ1-@VARIANT$+KCNE1), which reconstitute the slow delayed rectifier potassium current (IKs). The functional consequence of KCNH2-p.C108Y was investigated by analyzing the ionic currents from cells expressing @GENE$-WT or KCNH2-@VARIANT$ and from cells co-expressing both alleles. 5578023 KCNQ1;85014 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 0 -Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of @GENE$ were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD. 8446458 SEMA7A;2678 PROKR2;16368 c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482 c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709 0 -Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. 2737700 GJB2;2975 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -This analysis indicated that the CAPN3 variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the DES gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient. 6180278 CAPN3;52 DES;56469 rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448 rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249 1 -The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B). 3842385 EDA;1896 WNT10A;22525 p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -(A) Segregation of the @GENE$-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members. 5578023 KCNQ1;85014 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Genotypes: @GENE$ p.Thr1100Met (@VARIANT$; blue); @GENE$ @VARIANT$ (Y179C; green); -, wild type. 7689793 MSH6;149 MUTYH;8156 T1100M;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473 p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475 0 -Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331 0 -(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous p.A194T mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). 4998745 GJB2;2975 GJB3;7338 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6). 6610752 KCNH2;201 KCNE2;71688 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 1 -RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Three variants in three genes were rare, including the @GENE$ gene mutation [@VARIANT$], a novel heterozygous missense variant [@VARIANT$; p.(Glu436Lys)] in the @GENE$ gene (NM_001146029), as well as a splice site variation in the PLXNA1 gene (NM_032242; MAF = 0.03 in GnomAD). 8446458 PROKR2;16368 SEMA7A;2678 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -(a) Digenic inheritance of @GENE$ (@VARIANT$, C104R TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ @VARIANT$ mutation (as indicated). 5671988 TNFRSF13B;49320 TCF3;2408 c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDN3;88 EDNRB;89 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 7689793 TRIP6;37757 CAPN9;38208 p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675 c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$). 3888818 KAL1;55445 TACR3;824 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene. 6707335 ALS2;23264 DYNC1H1;1053 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051 0 -Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX @VARIANT$ and SETX p.T14I). 4293318 SOD1;392 FUS;2521 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108 0 -A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven. Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous @GENE$ and @GENE$ variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy. 5868303 TIA1;20692 SQSTM1;31202 c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired) c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 1 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 - In patient AVM427, the de novo heterozygous missense variant @VARIANT$ (p.Asp1148Tyr) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to Smad1-mediated @GENE$ signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-@GENE$ complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, @VARIANT$ (p.Glu631Ter), in EGFR (table 1). 6161649 BMP;55955 Smad4;31310 c.3442G>T;tmVar:c|SUB|G|3442|T;HGVS:c.3442G>T;VariantGroup:3;CorrespondingGene:9765 c.1891G>T;tmVar:c|SUB|G|1891|T;HGVS:c.1891G>T;VariantGroup:8;RS#:909905659 0 -Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). 5887939 CELSR1;7665 DVL3;20928 c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808 c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited. 6371743 MBD5;81861 NRXN1;21005 c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620 c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814 0 -Four genes (including AGXT2, @GENE$, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies. 5725008 ZFHX3;21366 SCAP;8160 p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 -Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 TYRO3;4585 SNAI3;8500 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The mutations of @GENE$ @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous @GENE$ @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a). 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation. 6610752 KCNE2;71688 KCNH2;201 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 0 -A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in @GENE$ and a missense variant @VARIANT$ (p.Leu593Val) in @GENE$. Limited clinical information was available about this male. 7463850 EHMT1;11698 SLC9A6;55971 p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502 c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465 1 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 MITF;4892 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 CYP1B1;68035 TEK;397 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe). 6567512 BBS1;11641 BBS2;12122 c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583 c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). 8152424 DDB1 and CUL4 associated factor 17;80067;1642 DCAF17;65979 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in USH2A. 3125325 MYO7A;219 USH1C;77476 c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415 c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060 0 - CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway. 7549550 MYOD1;7857 TBX6;3389 c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491 c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682 0 -Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and KCNQ1-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. Primers used for mutagenesis are available upon request. The KCNH2-WT, @GENE$-WT, and mutant coding sequences were engineered in bicistronic mammalian vectors pIRES2-EGFP (Biosciences-Clontech, Palo Alto, CA, USA). 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -A total of 2 novel variants, p.S309P and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. @VARIANT$ is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and p.K618* are located in the cytoplasmic loops (Fig. S3C). Patients with GIS had a higher tendency to be affected with mutations than patients with TD [25/32 (78%) vs. 6/11 (54%), Fig. 2]. Variants in TG, @GENE$, DUOXA2, SLC5A5 and PROP1 genes were found exclusively in patients with GIS, and 1 variant in TRHR was found in patients with TD. Other genes, including DUOX2, TPO and @GENE$, were associated with either dysgenesis or GIS phenotype (Table II and Fig. 1B). 7248516 TSHR;315 SLC26A4;20132 p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605 p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116 0 -"Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes. ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of WNT10A were detected." 3842385 WNT10A;22525 EDA;1896 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657 0 -Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 DVL3;20928 p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181 p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292 0 -These include complete conservation of @VARIANT$ (Figures S1-S4), SIFT analysis, and protein modeling. Furthermore, protein expression was markedly reduced in vitro, providing additional support for a deleterious effect. This patient with the p.Ala253Thr @GENE$ missense mutation also had a hemizygous @GENE$ deletion of the completely conserved @VARIANT$ within the whey-acidic-protein (WAP) domain that forms a disulphide bridge with Cys134 of anosmin-1 (Figure S1C,D). 3888818 NELF;10648 KAL1;55445 Ala253;tmVar:p|Allele|A|253;VariantGroup:3;CorrespondingGene:26012;RS#:142726563 Cys163;tmVar:p|Allele|C|163;VariantGroup:9;CorrespondingGene:3730 0 -The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. 3842385 EDA;1896 WNT10A;22525 termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, @VARIANT$ in @GENE$, and c.2299delG and @VARIANT$ in USH2A. 3125325 MYO7A;219 USH1C;77476 c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647 c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060 0 -(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within @GENE$, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3). 6161649 SMAD1;21196 BMP;55955 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation. 6610752 LQT6;71688 KCNH2;201 c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221 p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493 0 -Because charged residues are important for proteins trafficking, the A194T may result in accumulation of the @GENE$ protein in intracellular compartments such as the Golgi apparatus or in other sites such as the endoplasmic reticulum or lysosomes. The A194T substitution might cause conformational changes within the Cx31 molecule or affect the ability of Cx31 to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in Cx26 as well as @VARIANT$, S198F and G199R in @GENE$, have been reported previously in patients with hearing impairment. 2737700 Cx31;7338 Cx32;137 N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851 F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 KAL1;55445 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, @GENE$-@VARIANT$, and KCNE1-@VARIANT$ could be LQTS modifiers. 5578023 KCNQ1;85014 KCNH2;201 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in @GENE$, ANOS1, @GENE$, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. 8446458 DUSP6;55621 DCC;21081 Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050 Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 MITF;4892 SNAI3;8500 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 - In a second example, we identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014). Additionally, the @VARIANT$ @GENE$ change has been previously found to be causative of micropenis, where it was found in compound heterozygosity or homozygosity in three individuals (Sasaki et al., 2003). 5765430 SF1;138518 SRD5A2;37292 single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536 p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681 0 -In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in @GENE$ (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in @GENE$ (@VARIANT$; @VARIANT$). 6359299 LAMA4;37604 MYH7;68044 c.2770G > A;tmVar:c|SUB|G|2770|A;HGVS:c.2770G>A;VariantGroup:0;CorrespondingGene:3910;RS#:121913628;CA#:13034 p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034 0 -None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:@VARIANT$; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a). 6053831 PCDH15;23401 USH1G;56113 55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217 72915838C > T;tmVar:g|SUB|C|72915838|T;HGVS:g.72915838C>T;VariantGroup:1;CorrespondingGene:124590;RS#:538983393;CA#:8753931 1 -Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations. 7067772 pendrin;20132 EPHA2;20929 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403 0 -In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. 6161649 ENG;92 VEGFR2;55639 p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778 c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588 0 -Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and KCNQ1-c.G1748A (@VARIANT$) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously. 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -Mutations in the @GENE$ and @GENE$ Genes in a Family with Pseudoxanthoma Elasticum-like Phenotypes A characteristic feature of classic PXE, an autosomal recessive disorder caused by mutations in the ABCC6 gene, is aberrant mineralization of connective tissues, particularly the elastic fibers. Here, we report a family with PXE-like cutaneous features in association with multiple coagulation factor deficiency, an autosomal recessive disorder associated with GGCX mutations. The proband and her sister, both with severe skin findings with extensive mineralization, were compound heterozygotes for missense mutations in the GGCX gene, which were shown to result in reduced gamma-glutamyl carboxylase activity and in under-carboxylation of matrix gla protein. The proband's mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (@VARIANT$) in GGCX and a null mutation (@VARIANT$) in the ABCC6 gene, suggesting digenic nature of their skin findings. 2900916 GGCX;639 ABCC6;55559 p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 1 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 DCTN1;3011 FUS;2521 p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583 p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390 0 -20 The identified CUX1 (NM_001202543: @VARIANT$, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include @GENE$, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 7689793 RYR3;68151 CAPN9;38208 c.1438A > G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849 p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919 0 -Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS. 8621929 LRP6;1747 WNT10A;22525 rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A). 5887939 FZD1;20750 FAT4;14377 c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903 c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652 0 -Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). 2737700 Cx31;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different @GENE$ mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. 5868303 TIA1;20692 SQSTM1;31202 c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired) c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 1 -For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug @GENE$-WT or 1 mug KCNQ1-@VARIANT$ + 1 mug KCNE1-WT) or 3 mug (1.5 mug KCNH2-WT + 1.5 mug KCNH2-@VARIANT$ or 1.5 mug @GENE$-WT + 1.5 mug empty vector) plasmid per dish were used. 5578023 KCNE1;3753 KCNH2;201 c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757 0 -Pedigree and sequence chromatograms of the patient with the @VARIANT$ in @GENE$ and c.158-1G>A in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in MYO7A. Another variation, @VARIANT$ in intron 3 of PCDH15, was derived from the proband and his father. 3949687 MYO7A;219 PCDH15;23401 p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 0 -(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. 4998745 GJB3;7338 GJB6;4936 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$). 6567512 BBS2;12122 BBS7;12395 c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582 Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea. 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3). 3888818 KAL1;55445 NELF;10648 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDNRB;89 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal @GENE$ domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary CYP1B1-binding site. 5953556 CYP1B1;68035 TEK;397 E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010 0 -Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and @GENE$ p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. 8739608 LAMA2;37306 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757 0 -On the other hand, mis-localization of @GENE$ A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding. Here, we found that pendrin A372V, L445W, Q446R, and @VARIANT$ did not bind to EphA2. Given the fact that loss of @GENE$ disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation. 7067772 pendrin;20132 EphA2;20929 G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 - In patient AVM359, the de novo heterozygous missense variant c.1592G>A (p.Cys531Tyr) was identified in @GENE$ (table 1), which encodes a membrane-associated multidomain protein. The variant is predicted to affect a conserved site (SIFT=0, PolyPhen2=1, GERP++=5.68, CADD=24.6). SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within @GENE$, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). 6161649 SCUBE2;36383 SMAD1;21196 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 0 -The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene. 6707335 ALS2;23264 MATR3;7830 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051 0 -Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. 5953556 TEK;397 CYP1B1;68035 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 0 -The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of PROKR2 were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD. 8446458 DUSP6;55621 SEMA7A;2678 p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482 c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709 0 -Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. 3426548 PROK2;9268 FGFR1;69065 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired) 0 - Recently, Gifford et al., identified three missense variants in @GENE$ (Gln670His), @GENE$ (@VARIANT$), and NKX2-5 (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019). 7057083 MKL2;40917 MYH7;68044 Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625 Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058 0 -However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of @GENE$ protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction. LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and SCN5A @VARIANT$ by WES and predisposing genes analyses. 8739608 KCNH2;201 Nav1.5;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -@GENE$-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNQ1;85014 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. 4998745 gap junction protein beta 2;2975 GJB3;7338 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 0 -Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and @VARIANT$; @GENE$: @VARIANT$). In summary, the increased frequency in PCG patients of rare @GENE$ and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG. 6338360 PITX2;55454 FOXC2;21091 p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) 0 -None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; @VARIANT$] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a). The @GENE$ variant [NM_033056: c.3101G > A; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892). 6053831 USH1G;56113 PCDH15;23401 55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217 p.(Arg1034His);tmVar:p|SUB|R|1034|H;HGVS:p.R1034H;VariantGroup:2;CorrespondingGene:124590 0 -(A) In addition to c.235delC in GJB2, the de novo variant of @GENE$, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous p.A194T mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). 4998745 MITF;4892 GJB2;2975 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 SNAI3;8500 TYRO3;4585 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. 3842385 EDA;1896 WNT10A;22525 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 @VARIANT$, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS. 8621929 LRP6;1747 WNT10A;22525 c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462 rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216 0 -In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene. 6707335 SPG11;41614 UBQLN2;81830 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -M1, CYP1B1: @VARIANT$. M2, @GENE$: p.(E387K). M3, CYP1B1: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases. 6338360 CYP1B1;68035 PITX2;55454 p.(A179fs*18);tmVar:p|FS|A|179||18;HGVS:p.A179fsX18;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 0 -The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. 6637284 ISG20L2;12814 S100A3;2223 p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284 0 -@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, @VARIANT$ of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1). 4998745 GJB2;2975 TMC1;23670 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.W482R;tmVar:p|SUB|W|482|R;HGVS:p.W482R;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956 1 - Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the @GENE$ gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the HNF1A variant was present in the mother (Figure 1B). 8306687 HNF1A;459 GCK;55440 p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645 p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336 0 -It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and @VARIANT$, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed. 5611365 CYP1B1;68035 MYOC;220 p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416 p.R170W;tmVar:p|SUB|R|170|W;HGVS:p.R170W;VariantGroup:59;CorrespondingGene:1805 0 -Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ @VARIANT$, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 DVL3;20928 p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026 p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085 0 -Because charged residues are important for proteins trafficking, the @VARIANT$ may result in accumulation of the Cx31 protein in intracellular compartments such as the Golgi apparatus or in other sites such as the endoplasmic reticulum or lysosomes. The A194T substitution might cause conformational changes within the @GENE$ molecule or affect the ability of Cx31 to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and @VARIANT$ in @GENE$ as well as F193C, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment. 2737700 Cx31;7338 Cx26;2975 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 A197S;tmVar:p|SUB|A|197|S;HGVS:p.A197S;VariantGroup:3;CorrespondingGene:2706;RS#:777236559 0 - The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined. 7067772 pendrin;20132 EphA2;20929 F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 MITF;4892 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. 6161649 ENG;92 VEGFR2;55639 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588 0 -A complete loss of this trans-activational activity was noted for the proteins with missense mutations located in the LBD (@VARIANT$ and p.Asp364Tyr), the SF1 @VARIANT$, as well as both frame-shift mutations assayed (p.Arg89Glyfs*17 and p.Leu209Cysfs*87) (Figure 3). Intriguingly, a nonsense SF1 variant (p.[Pro210Gln;Tyr211*]) seemed to retain a low level of activity (Figure 3). A similar pattern was seen with the SRY/SF1 transfected cells; however, the magnitude of activation was in general lower than that of the SOX9/SF1 transfection (Figure 3). All the @GENE$ variants identified in our DSD patients showed reduced transactivation activity in vitro when co-transfected with SRY or @GENE$. This suggests that the reason these variants are pathogenic is because they result in a dramatic reduction or loss of SF1 transactivation activity in these patients. 5765430 SF1;138518 SOX9;294 p.His310Asp;tmVar:p|SUB|H|310|D;HGVS:p.H310D;VariantGroup:4;CorrespondingGene:6662;RS#:780987236;CA#:8739053 p.47_54del;tmVar:p|DEL|47_54|;HGVS:p.47_54del;VariantGroup:30;CorrespondingGene:2516 0 -Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of @GENE$ @VARIANT$ increased, which thus lead to a reduction of structural stability. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 - Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. 6707335 SPG11;41614 ubiquilin-2;81830 L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus lead to a reduction of structural stability. However, SCN5A @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d). The MFE of @GENE$ p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure. RNA secondary structural prediction. (a, b) Compared with wild-type KCNH2, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus led to a reduction of structural stability. 8739608 SCN5A;22738 KCNH2;201 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3). 3888818 NELF;10648 KAL1;55445 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 0 -Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 - Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. 6707335 SPG11;41614 UBQLN2;81830 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -Given the reported normal function of @GENE$ L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). 7067772 pendrin;20132 EphA2;20929 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 0 -Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. 6371743 NRXN1;21005 NRXN2;86984 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 0 -RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). 2737700 Cx26;2975 GJB3;7338 A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Among sensorineural hearing loss patients EVA or the Pendred syndrome patients, a considerable number of patients carry one copy of the mutation on the @GENE$ gene, therefore a compromised pendrin regulatory machinery may be involved in the pathogenesis of the syndrome. To further analyze the role of EphA2 in Pendred syndrome, direct sequencing of the EPHA2 gene in 40 Japanese hearing loss patients with EVA carrying mono-allelic mutation of SLC26A4 were examined. While mutation of ~70 genes causing hearing loss were previously identified as a human nonsyndromic deafness gene, they were not identified in these patients. On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), @GENE$: c.1532C>T (@VARIANT$) (Fig. 6a, b). These EPHA2 mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of SLC26A4 was previously reported. 7067772 SLC26A4;20132 EPHA2;20929 p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772 0 -M2, @GENE$: p.(E387K). M3, CYP1B1: @VARIANT$. M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases. 6338360 CYP1B1;68035 PITX2;55454 p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 0 -These two individuals were heterozygous carriers of @VARIANT$ mutation in ABCC6 and p.V255M in GGCX. Since heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. In this case, haploinsufficiency of the carboxylase activity and reduced ABCC6 functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (p.R1141X) and the @GENE$ gene (@VARIANT$) yet did not display any cutaneous findings are not clear. 2900916 ABCC6;55559 GGCX;639 p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115 p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS. The novel @GENE$ @VARIANT$ mutation substitutes the hydrophobic methionine168 for an arginine (p.Met168Arg) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1." 8621929 WNT10A;22525 LRP6;1747 c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313 c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040 0 -Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -M3, @GENE$: @VARIANT$. M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases. 6338360 CYP1B1;68035 PITX2;55454 p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 0 -Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 HS1BP3;10980 CAPN11;21392 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively. 2737700 GJB3;7338 GJB2;2975 asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204 0 -To investigate possible oligogenic inheritance involving FOXC2 or @GENE$ and @GENE$, we also analyzed FOXC2 and PITX2 variants in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare FOXC2 variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: @VARIANT$, p.(H395N); and PITX2: @VARIANT$, p.(P179T)) have not been previously identified. 6338360 PITX2;55454 CYP1B1;68035 c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303 c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -Therefore, we may speculate that the functional defect of @GENE$-@VARIANT$ could be compromised conductance. Interestingly, it has been reported that the KCNH2-p.C66G variant, located in the PAS domain, reaches the cell surface, but it remains in the immature form and is non-conducting. On the contrary, the functionality of the KCNQ1-p.R583H channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNH2;201 KCNE1;3753 C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), @GENE$ (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). 3125325 MYO7A;219 USH1G;56113 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 1 -Moreover, similar truncations in the highly homologous DUOX2 [p.Q686*, p.R701*, @VARIANT$;(IVS19-2A>C), p.S965fsX994] are associated with CH or severely impaired H2O2-generating activity in vitro. The @VARIANT$ mutation would be predicted to generate a nonfunctional DUOX1 enzyme, and its digenic inheritance alongside the homozygous @GENE$ p.R434* will likely result in complete absence of functional DUOX isoenzyme in our patients. It has been speculated that @GENE$ upregulation in the context of DUOX2 loss of function may at least partially compensate for defective H2O2 production. 5587079 DUOX2;9689 DUOX1;68136 p.(G418fsX482);tmVar:p|FS|G|418||482;HGVS:p.G418fsX482;VariantGroup:2;CorrespondingGene:50506 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 0 -Three variants in three genes were rare, including the @GENE$ gene mutation [@VARIANT$], a novel heterozygous missense variant [c.1801G > A; p.(@VARIANT$)] in the SEMA7A gene (NM_001146029), as well as a splice site variation in the @GENE$ gene (NM_032242; MAF = 0.03 in GnomAD). 8446458 PROKR2;16368 PLXNA1;56426 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050 0 -The genotypes of SLC20A2 (NM_001257180.2: @VARIANT$, p.His596Arg) and PDGFRB (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type. 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). 2737700 GJB3;7338 GJB2;2975 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the @GENE$ protein (c.229C>T; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts. 6637284 S100A3;2223 S100A13;7523 arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284 c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284 0 -Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. 8739608 SCN5A;22738 KCNH2;201 c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099 c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331 0 -Pedigree and sequence chromatograms of the patient with the @VARIANT$ in MYO7A and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father. 3949687 MYO7A;219 PCDH15;23401 p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 1 -The c.1787A>G (@VARIANT$) mutation of @GENE$ has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The c.317G>C (p.Arg106Pro) variant of @GENE$, a rare single nucleotide polymorphism (SNP, @VARIANT$), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown). 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (@VARIANT$;[=]) (p.Arg80Cys) in the @GENE$ gene. The GNRHR frameshift mutation was identified in two different families and has not been reported before. It consists of an 11 base-pair deletion (@VARIANT$), and if translated, would be expected to result in a truncated protein due to a premature termination codon (p.Phe313Metfs*3). 5527354 GNRHR;350 PROKR2;16368 c.[238C > T];tmVar:c|SUB|C|238|T;HGVS:c.238C>T;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400 c.937_947delTTTTTAAACCC;tmVar:c|DEL|937_947|TTTTTAAACCC;HGVS:c.937_947delTTTTTAAACCC;VariantGroup:7;CorrespondingGene:2798 0 -There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes. 6565573 COL4A3;68033 COL4A4;20071 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174 0 - DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. 8172206 SLC20A2;68531 PDGFRB;1960 p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575 p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 0 -In addition, we found an elevated frequency (8%) of heterozygous and rare @GENE$ variants in the group of CG cases who were known to carry @GENE$ glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, @VARIANT$) have not been previously identified. 6338360 PITX2;55454 CYP1B1;68035 p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873 0 -(A) In addition to @VARIANT$ in @GENE$, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus. 4998745 GJB2;2975 GJB6;4936 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. 4293318 SOD1;392 VAPB;36163 p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 0 - Aberrant regulation of pathogenic forms of @GENE$ via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of @GENE$ with mutated pendrin. myc-pendrin A372V, @VARIANT$, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected. 7067772 pendrin;20132 EphA2;20929 L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). 2737700 GJB2;2975 GJB3;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). 8446458 PROKR2;16368 SEMA7A;2678 p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674 p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482 0 -c, d Immunoprecipitation of @GENE$ with mutated @GENE$. Immunocomplex of myc-pendrin L117F, @VARIANT$ and @VARIANT$ was not affected. 7067772 EphA2;20929 pendrin;20132 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). 3888818 NELF;10648 TACR3;824 c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871 0 -Nevertheless, the @VARIANT$ variant has also been considered a benign variant, due to its association with close to normal life expectancy (Tripathi et al., 2011). Recently, Gifford et al., identified three missense variants in @GENE$ (@VARIANT$), @GENE$ (Leu387Phe), and NKX2-5 (Ala119Ser) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019). 7057083 MKL2;40917 MYH7;68044 p.Ile736Thr;tmVar:p|SUB|I|736|T;HGVS:p.I736T;VariantGroup:1;CorrespondingGene:4625;RS#:727503261(Expired) Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496 0 -Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. 8739608 LAMA2;37306 SCN5A;22738 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757 0 - Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. 6707335 SPG11;41614 UBQLN2;81830 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -Mutations in @GENE$ and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. 6371743 NRXN1;21005 NRXN2;86984 p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143 c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of @GENE$). 3888818 NELF;10648 TACR3;824 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871 0 - In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. 6161649 PTPN13;7909 MAP4K4;7442 p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566 p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588 0 -Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees. 6081235 DNAH17;72102 MYOD1;7857 p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211 c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615 0 -(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. 4998745 gap junction protein beta 2;2975 gap junction protein beta 3;7338 p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706 p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -The two variants chr18:77170979 G>A for @GENE$ and chr1:@VARIANT$ for @GENE$ lead to novel missense variants, p.R222Q and @VARIANT$ respectively. 5611365 NFATC1;32336 OBSCN;70869 228462101 G>A;tmVar:c|SUB|G|228462101|A;HGVS:c.228462101G>A;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692 p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. 3842385 EDA;1896 WNT10A;22525 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -II: 1 carried the digenic heterozygous mutations of @GENE$ @VARIANT$ and SCN5A @VARIANT$. I: 1 and II: 2 were heterozygous for @GENE$ p.R1865H. 8739608 KCNH2;201 SCN5A;22738 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out. 8152424 FGFR1;69065 CCDC88C;18903 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192 1 - Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein. 6707335 SPG11;41614 FUS;2521 R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-@GENE$ Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type @GENE$ and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. 5953556 TEK;397 CYP1B1;68035 G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -The @VARIANT$ mutation in the @GENE$ gene segregated with the LVNC phenotype in the examined family. It was also found in one unrelated patient affected by LVNC, confirming a causative role in cardiomyopathy. The @VARIANT$ mutation in the @GENE$ gene, a key component of the basal lamina of muscle fibers, was found only in the proband, suggesting a role in CFTD. 3695851 MYH7B;66117 ITGA7;37592 R890C;tmVar:p|SUB|R|890|C;HGVS:p.R890C;VariantGroup:4;CorrespondingGene:57644;RS#:186471205 E882K;tmVar:p|SUB|E|882|K;HGVS:p.E882K;VariantGroup:1;CorrespondingGene:3679;RS#:144983062;CA#:147560 1 -Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in @GENE$, ANOS1, DCC, @GENE$, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. 8446458 DUSP6;55621 PLXNA1;56426 Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050 Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072 0 -Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G). 3125325 MYO7A;219 USH2A;66151 p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. 3842385 EDA;1896 WNT10A;22525 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 1 -The mother and son reported by Beijers et al. were heterozygous for @GENE$ @VARIANT$ and @GENE$ @VARIANT$, but the G31D substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/). 4090307 HNF1A;459 HNF4A;395 G31D;tmVar:p|SUB|G|31|D;HGVS:p.G31D;VariantGroup:4;CorrespondingGene:6927;RS#:137853247;CA#:124487 H214Y;tmVar:p|SUB|H|214|Y;HGVS:p.H214Y;VariantGroup:5;CorrespondingGene:3172 1 -On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), @GENE$: @VARIANT$ (p.T511M) (Fig. 6a, b). 7067772 SLC26A4;20132 EPHA2;20929 p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772 c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151 0 - In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to @GENE$-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-@GENE$ complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, @VARIANT$ (p.Glu631Ter), in EGFR (table 1). 6161649 Smad1;21196 Smad4;31310 p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765 c.1891G>T;tmVar:c|SUB|G|1891|T;HGVS:c.1891G>T;VariantGroup:8;RS#:909905659 0 -Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. 5953556 TEK;397 CYP1B1;68035 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 1 -Mutations affecting these regions have also been reported in @GENE$ underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in Cx26 as well as @VARIANT$, @VARIANT$ and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (@GENE$, Cx31, and Cx32) suggested that the EC2 and TM4 domains are important to the function of the Cx31 protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear. 2737700 Cx32;137 Cx26;2975 F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706 S198F;tmVar:p|SUB|S|198|F;HGVS:p.S198F;VariantGroup:14;CorrespondingGene:2705 0 -A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited. 6371743 MBD5;81861 NRXN1;21005 p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620 c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814 0 -Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, @VARIANT$ (c.475A > G p. S159G) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature. 3975370 NOD2;11156 IL10RA;1196 2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322 rs3135932;tmVar:rs3135932;VariantGroup:0;CorrespondingGene:3587;RS#:3135932 0 -"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -No mutations in @GENE$, @GENE$, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient. 6098846 SLC5A5;37311 TPO;461 c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155 p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391 0 -According to earlier studies, @GENE$ variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. 6707335 KIF5A;55861 SPG11;41614 E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063 E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795 0 -Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E). 7279190 FLNB;37480 TTC26;11786 p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989 p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246 0 -Pedigree and sequence chromatograms of the patient with the @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$ mutations. 3949687 MYO7A;219 PCDH15;23401 p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 1 -This patient with the @VARIANT$ @GENE$ missense mutation also had a hemizygous KAL1 deletion of the completely conserved @VARIANT$ within the whey-acidic-protein (WAP) domain that forms a disulphide bridge with Cys134 of @GENE$ (Figure S1C,D). 3888818 NELF;10648 anosmin-1;55445 p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407 Cys163;tmVar:p|Allele|C|163;VariantGroup:9;CorrespondingGene:3730 0 -Four genes (including @GENE$, ZFHX3, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and AGXT2-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies. 5725008 AGXT2;12887 SCAP;8160 c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937 c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SOX10;5055 TYRO3;4585 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -These results suggest an important role of @GENE$ as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of @GENE$. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected. 7067772 ephrin-B2;3019 ephrin-A1;3262 A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049 E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$). 4293318 VAPB;36163 SETX;41003 p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276 p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953 0 -Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::@GENE$ (p.A115P), @GENE$ (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction. 5953556 CYP1B1;68035 TEK;397 p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. 6707335 GRN;1577 SQSTM1;31202 R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852 I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068 0 -Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes. 6565573 COL4A4;20071 COL4A3;68033 c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287 Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204 0 -On the other hand, mutant GFP-@GENE$ A115P and @VARIANT$ showed perturbed interaction with HA-TEK. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of @GENE$ (Fig. 1d). 5953556 CYP1B1;68035 TEK;397 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010 0 -@GENE$ @VARIANT$ but not @GENE$-gamma @VARIANT$ causes renal defects in Drosophila The fly kidney is composed of garland and pericardial nephrocytes (Fig 6A) that perform the filtration of the hemolymph and Malpighian tubules that function as excretory tubes. 5973622 KAT2B;20834 adducin;22758 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 0 -The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. 6707335 alsin;23264 MATR3;7830 R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683 R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559 0 -Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 HS1BP3;10980 TRPV4;11003 c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -In order to evaluate the likelihood of @GENE$ and @GENE$ to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients). Using these filtering settings, no variants in OPTN or TBK1 were detected in any of our control datasets which emphasizes that the presence of rare double hits in our FTLD-TDP cohort is unlikely to have occurred by chance alone. Comparison of sequence traces of OPTN exon 8 (harboring the @VARIANT$ mutation) in gDNA and mRNA prepared from cerebellar cortex of case A showed the absence of mutant RNA (T-allele) suggesting the degradation of mutant RNA by nonsense mediated decay (Figure 1c). A similar analysis of OPTN exon 14 (harboring the @VARIANT$) mutation showed significantly reduced amounts of the wild-type (C-allele) in the cDNA sequence suggesting that the missense variant was inherited in trans with respect to the OPTN nonsense mutation (Figure 1c). 4470809 OPTN;11085 TBK1;22742 p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970 0 -Pathogenic effects of GBE1 D413N and @GENE$ @VARIANT$ variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ @VARIANT$ variant in MH. 6072915 NDUFS8;1867 RYR1;68069 I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290 p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146 0 -We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). A compound heterozygous TEK mutation (p.E103D and p.E300G) was also observed in 1 family (PCG38). However, the remaining 20 PCG cases harboring a single heterozygous TEK mutation did not carry any additional mutation in the other 35 adult and childhood glaucoma-associated genes (Supplementary Fig. 1; Supplementary Table 1). The co-occurrence of heterozygous @GENE$ and CYP1B1 mutations as seen in our PCG cases were not observed in additional sets of POAG, ARS, Aniridia, and Peter's Anomaly patients. 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. 6707335 SPG11;41614 UBQLN2;81830 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978 0 -She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the @GENE$ locus (Figure 4B). The @VARIANT$ residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). 4998745 DFNB1;2975 MITF;4892 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a). 2737700 GJB2;2975 GJB3;7338 A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Two potential disease-causing mutations were identified: (d) @GENE$: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) @GENE$ missense mutation c.1559G>A/@VARIANT$. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (ENAM and LAMA3) mutations. 6785452 ENAM;9698 LAMA3;18279 c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801 p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909 1 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$). 6610752 LQT2;201 LQT6;71688 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 0 -Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/@GENE$ @VARIANT$ mutations are shown. 5671988 TCF3;2408 TACI;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 1 - Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a @VARIANT$ (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). 2900916 GGCX;639 VKORC1;11416 c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442 valine by methionine at position 255;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957 0 -(A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326 0 -Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (rs144901249) genes. 6180278 COL6A3;37917 DES;56469 rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558 rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685 0 -Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (@VARIANT$, p.G505D). A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H). 6098846 TG;2430 DUOXA2;57037 c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370 c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341 1 -The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the @GENE$/TACI C104R mutation. 5671988 TCF3;2408 TNFRSF13B;49320 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 0 -In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). 2737700 GJB3;7338 GJB2;2975 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons. 2737700 Cx26;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons. 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. 5953556 TEK;397 CYP1B1;68035 p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 PAX3;22494 TYRO3;4585 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Missense and non-sense were the most frequent variants in both genes, followed by frameshift in @GENE$ and by splicing and frameshift in @GENE$. Six variants in PKD1 occurred de-novo, three of which were not previously described: c.3236del p.(Asp1079Alafs*25), @VARIANT$ p.(Glu2954*), and @VARIANT$. One de-novo and novel variant was also detected in PKD2: c.992G>A p.(Cys331Tyr). 7224062 PKD1;250 PKD2;20104 c.8860G>T;tmVar:c|SUB|G|8860|T;HGVS:c.8860G>T;VariantGroup:46;CorrespondingGene:5310 c.9201+1G>A;tmVar:c|SUB|G|9201+1|A;HGVS:c.9201+1G>A;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907 0 -Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. 6371743 NRXN1;21005 NRXN2;86984 c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143 p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001 1 -Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, R127W (@VARIANT$) and a heterozygous frameshift mutation in exon 4 of @GENE$, P291fsinsC (@VARIANT$). 4090307 HNF4A;395 HNF1A;459 c.379C>T;tmVar:c|SUB|C|379|T;HGVS:c.379C>T;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226 c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825 1 -To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined. 7067772 pendrin;20132 EphA2;20929 L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6. 6610752 LQT6;71688 LQT2;201 c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992 p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757 0 -Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees. 6081235 UNC13B;31376 SPTBN4;11879 p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342 c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137 0 -Note that subject II:1 in family PCG-133 was diagnosed at the age of 3 months and carried the de novo @VARIANT$ PITX2 variant, whereas his brother, who did not carry this variant, was diagnosed at the age of 10 years. The proband in family PCG-139 also carried a rare PITX2 variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, @GENE$: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: p.(A188T). 6338360 CYP1B1;68035 PITX2;55454 p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 0 -Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, @GENE$ @VARIANT$ (p.Leu10Met) and @GENE$ c.742C > T (@VARIANT$). 7463850 GRIN2A;645 PLXNB2;66630 c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903 p.Arg248Cys;tmVar:p|SUB|R|248|C;HGVS:p.R248C;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520 0 -After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, @VARIANT$ in @GENE$ and @VARIANT$ in S100A3, and one novel variant in @GENE$, were identified. 6637284 SETDB1;32157 S100A13;7523 rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912 rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706 0 -SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for @GENE$ and KCNH2 mutations. KCNH2 p.307_308del and SCN5A @VARIANT$ of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus lead to a reduction of structural stability. 8739608 SCN5A;22738 KCNH2;201 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -"Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys." 3842385 WNT10A;22525 EDA;1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired) 0 -Patient P0418 carries a nonsense mutation in @GENE$ (@VARIANT$) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. 3125325 USH2A;66151 MYO7A;219 p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795 p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406 1 - Cardiac Phenotype: A FOXC1/@GENE$ Genetic Interaction The cardiac phenotype in the indexed-family is divided into two: a mild VSD not requiring any intervention and a severe TOF-like phenotype that required major intervention (Figure 1). We sought that differential variants inherited from the father would contribute to this differential expressivity of the ARS phenotype within the three affected children in this family: two with a cardiac phenotype and the third with only glaucoma. Interestingly, we unravel two novel missense mutations in @GENE$ (@VARIANT$) and NFATC1 (@VARIANT$) that are predicted to be damaging (Table 4). 5611365 NFATC1;32336 OBSCN;70869 p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033 p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. 3842385 EDA;1896 WNT10A;22525 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 - A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). 7463850 EHMT1;11698 MFSD8;115814 c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656 c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496 1 -For example, two variants in proband P15, @VARIANT$ in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. 8152424 DDB1 and CUL4 associated factor 17;80067;1642 DCAF17;65979 p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 0 -Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (c.1514G>A, p.G505D). A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H). 6098846 TG;2430 DUOXA2;57037 c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753 c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341 0 -We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). 5953556 CYP1B1;68035 TEK;397 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies. 5725008 SCAP;8160 AGXT2;12887 p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937 c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745 0 -To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. 7067772 EphA2;20929 pendrin;20132 L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985 F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409 0 -Moreover, the presence of other variants (@GENE$-@VARIANT$, @GENE$-@VARIANT$, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNQ1;85014 KCNH2;201 p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162 1 -The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B). 3842385 EDA;1896 WNT10A;22525 Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in OPTN and TBK1 and noted that case A carrying the @VARIANT$ nonsense variant in OPTN, is compound heterozygote for mutations in OPTN as it also carries the rare variant p.Ala481Val (NM_001008211.1:@VARIANT$) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34). In order to evaluate the likelihood of @GENE$ and @GENE$ to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients). 4470809 OPTN;11085 TBK1;22742 p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110 c.1442C>T;tmVar:c|SUB|C|1442|T;HGVS:c.1442C>T;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970 0 -All of them had confirmed hypogonadotropic hypogonadism and anosmia or hyposmia, and some already harbored a mutation in one of the five KS genes we had previously analyzed, specifically, in @GENE$ (13 patients), FGFR1 (30 patients), FGF8 (3 patients), PROKR2 (30 patients), or PROK2 (12 patients). Nonsynonymous mutations in @GENE$ were found in 24 patients (20 males and 4 females), all in heterozygous state (Table 1). They consist of a frameshifting deletion of 14 nucleotides (c.del1613_1626; p.D538fsX31), and seven different missense mutations (@VARIANT$, p.N153S, p.I400V, p.V435I, @VARIANT$, p.R730Q, p.R733H) that affect evolutionarily conserved aminoacid residues located in different domains of the protein (Figure 3). 3426548 KAL1;55445 SEMA3A;31358 p.R66W;tmVar:p|SUB|R|66|W;HGVS:p.R66W;VariantGroup:4;CorrespondingGene:10371;RS#:143241978 p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335 0 -Three SNPs in @GENE$ (@VARIANT$, rs543573, and rs2296871) were in perfect linkage disequilibrium and were considered to be one signal represented by rs2296871. We included only ALS subjects of European ancestry and compared to controls of European ancestry from ESP6500 and the 1000 Genomes Project. SPLINTER-predicted allele frequencies were used for common variants that were not confirmed by genotyping in ALS subjects. Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (rs3739927 and rs882709 in SETX, and @VARIANT$ in @GENE$). 4293318 SETX;41003 EWSR1;136069 rs1183768;tmVar:rs1183768;VariantGroup:64;CorrespondingGene:23064;RS#:1183768 rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143 0 -We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in BBS6, leading to the change p.(Cys412Phe). 6567512 BBS2;12122 BBS7;12395 stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279 c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 TYRO3;4585 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). 2737700 GJB2;2975 GJB3;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -These phenomenon indicate that the mutated @GENE$-@VARIANT$ (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-c.1103C>T (@VARIANT$) variant impaired the catabolism of ADMA in EA. 5725008 SCAP;8160 AGXT2;12887 c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937 p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$). 2737700 GJB2;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and @GENE$-@VARIANT$ (p.R583H) were introduced into @GENE$ and KCNQ1 cDNAs, respectively, as described previously. 5578023 KCNQ1;85014 KCNH2;201 c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757 c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304 0 -For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out. 8152424 CDON;22996 CCDC88C;18903 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 0 - @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene. 6707335 MATR3;7830 DYNC1H1;1053 P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187 T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778 0 -Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. 3125325 MYO7A;219 USH2A;66151 p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406 p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764 0 -Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 EDNRB;89 SNAI2;31127 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser." 3842385 WNT10A;22525 EDA;1896 c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 TYRO3;4585 MITF;4892 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 MITF;4892 SNAI3;8500 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/GJB3, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k). 2737700 GJB3;7338 GJB2;2975 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -c.235delC was recently reported to manifest a dynamic range of SNHL and a slightly milder audiologic phenotype compared with other @GENE$ variants in Koreans. Detection of mutations in MYO15A and @GENE$ in group I are relatively common in East Asian populations, including Koreans, indicating that application of panel sequencing covering the genes prioritized based on the ethnicity-specific prevalence would be effective for identifying GJB2 single heterozygotes with severe to profound SNHL in Koreans. For the family SH60 with a most likely genetic etiology but without a clear result after TES, whole exome sequencing can be used for definitive molecular diagnosis. This family SH60 segregates prelingual or perilingual severe to profound SNHL, likely in an autosomal dominant fashion, although prelingual SNHL of SH60-136 was caused by autosomal recessive mutations in other deafness genes (Figure 3). Further segregation analyses of the two variants (p.R143W and p.D771N) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both @VARIANT$ of GJB2 and @VARIANT$ of WFS1 as a molecular etiology of SH60-136. 4998745 GJB2;2975 TMC1;23670 p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234 p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681 0 -The proband in family PCG-139 also carried a rare @GENE$ variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, @GENE$: @VARIANT$. M3, CYP1B1: p.(E173*). 6338360 PITX2;55454 CYP1B1;68035 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241 0 -The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. 6707335 GRN;1577 SQSTM1;31202 R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049 C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519 0 -The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene. 6707335 ALS2;23264 MATR3;7830 G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568 G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051 0 -Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. 5953556 TEK;397 CYP1B1;68035 p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010 p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052 0 -Here, we found that @GENE$ A372V, @VARIANT$, Q446R, and G672E did not bind to EphA2. Given the fact that loss of EphA2 disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation. Multiple types of ephrin-A are expressed in the inner ear during development, meanwhile inner ear epithelial cell specific Efnb2 KO mice exhibit EVA-like malformation. While the function of ephrin-A5 in the inner ear was investigated, no reports have shown that any ephrin-A single KO mice show inner ear malformation. These observations suggest an indispensable role of @GENE$ in the morphology of the inner ear. 7067772 pendrin;20132 ephrin-B2;3019 L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309 S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 0 -Notably, our study has revealed one case of likely oligogenic inheritance for USH1, involving @GENE$ and USH1G, and possibly USH2A. Three cases of digenic inheritance of USH1 have been reported so far, all caused by mutations in @GENE$ and PCDH15, in agreement with the contribution of cadherin-23 and protocadherin-15 to the hair bundle transient lateral links and tip-links. The pathogenicity of the @VARIANT$ mutation in CDH23 is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (@VARIANT$) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention. 3125325 MYO7A;219 CDH23;11142 p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387 p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217 0 -In contrast to FGF inhibition, overexpression of IL17RD attenuates the degradation of epidermal growth factor recepter (@GENE$) and enhances downstream MAPK signalling (figure 3). In patient AVM457, a de novo heterozygous missense variant c.3355G>A (@VARIANT$) with a robust deleterious damaging predictions (SIFT=0.1, PolyPhen2=0.99, GERP++=4.33, CADD=29.3) was identified in PREX2 (table 1). PREX2 activates PI3K signalling via inhibition of phosphatase and tensin homolog (PTEN), and both germline and mosaic PTEN variants are associated with AVMs. In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating @GENE$ signalling. 6161649 EGFR;74545 BMP;55955 p.Ala1119Thr;tmVar:p|SUB|A|1119|T;HGVS:p.A1119T;VariantGroup:5;CorrespondingGene:80243;RS#:1212415588 p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765 0 -We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T). 2737700 GJB3;7338 GJB6;4936 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. 8152424 PROKR2;16368 DDB1 and CUL4 associated factor 17;80067;1642 p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487 c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260 0 -The patient carried a heterozygous variant of unknown significance in PKHD1, p.(@VARIANT$), defined as likely pathogenic in ClinVar, and a missense variant p.(@VARIANT$) in @GENE$, classified as likely pathogenic. Recessive mutations in PMM2 were reported as associated to hyperinsulinemic hypoglycemia (HI) and @GENE$ (Cabezas et al.,). 7224062 PMM2;257 PKD;55680 His3124Tyr;tmVar:p|SUB|H|3124|Y;HGVS:p.H3124Y;VariantGroup:17;CorrespondingGene:5314 Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 TYRO3;4585 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 - CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway. 7549550 MEOX1;3326 TBX6;3389 p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491 p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682 0 -The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). 3842385 EDA;1896 WNT10A;22525 Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 - The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. 7067772 pendrin;20132 EPHA2;20929 Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985 F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836 0 -Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). 8172206 SLC20A2;68531 PDGFRB;1960 c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575 c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083 1 -Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 MITF;4892 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). 2737700 Cx26;2975 Cx31;7338 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 1 -Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 TYRO3;4585 SNAI3;8500 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. 7877624 MITF;4892 SNAI3;8500 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 0 -CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the TNFRSF13B/@GENE$ C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 @VARIANT$ gene. 5671988 TCF3;2408 TACI;49320 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929 0 -However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure. RNA secondary structural prediction. (a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A @VARIANT$ showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability. 8739608 SCN5A;22738 KCNH2;201 p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757 p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651 0 -The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene. 6707335 ALS2;23264 MATR3;7830 S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809 G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051 0 -(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father). 3975370 IL10RA;1196 NOD2;11156 c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322 K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561 1 -The @GENE$ @VARIANT$ and @GENE$ @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. 5973622 ADD3;40893 KAT2B;20834 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 1 - Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). 8621929 LRP6;1747 WNT10A;22525 g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897 c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 1 -While both @GENE$ variants, p.(Ser127Thr) and p.(@VARIANT$), were inherited from her father, the @GENE$ mutation, @VARIANT$ was maternally derived. 8621929 LRP6;1747 WNT10A;22525 Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188 p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379 1 -Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. 5868303 SQSTM1;31202 TIA1;20692 c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired) p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407 1 -Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families. 5953556 TEK;397 CYP1B1;68035 p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449 p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 1 -Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). 8152424 CDON;22996 DCC;21081 p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125 p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919 0 -In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and @VARIANT$ (p.Gln989Leu) in @GENE$ (table 2). @GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina. 6161649 DSCAM;74393 DSCAML1;79549 c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588 c.2966A>T;tmVar:c|SUB|A|2966|T;HGVS:c.2966A>T;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588 0 - Human @GENE$ and KAT2B, were subcloned from human full-length cDNA (ADD3: clone IMAGE: 6649991; KAT2B clone IMAGE: 30333414) into the expression vectors pLentiGIII and PLEX-MCS, respectively. An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and KAT2B. The ADD3 @VARIANT$ and @GENE$ @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. 5973622 ADD3;40893 KAT2B;20834 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 MITF;4892 p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. 7877624 SOX10;5055 SNAI2;31127 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. 3842385 EDA;1896 WNT10A;22525 c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326 Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896 0 -In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. 6707335 SPG11;41614 UBQLN2;81830 A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493 L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -20 The identified @GENE$ (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 @GENE$, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 7689793 CUX1;22551 TRIP6;37757 c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919 p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675 0 -To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T). 2737700 GJB2;2975 Cx31;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 WNT10A;22525 EDA;1896 Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Total Serum Ig, clinical score and @GENE$/TACI @VARIANT$ and @GENE$ @VARIANT$ genotype for each family member, as indicated. 5671988 TNFRSF13B;49320 TCF3;2408 C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387 T161fsX191;tmVar:p|FS|T|161||191;HGVS:p.T161fsX191;VariantGroup:5;CorrespondingGene:6929 1 -The ADD3 @VARIANT$ and @GENE$ @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. All constructs were verified by sequencing. ADD3 or KAT2B depleted podocytes were transduced with WT or mutant @GENE$ or KAT2B lentiviral particles, respectively. 5973622 KAT2B;20834 ADD3;40893 E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787 F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850 0 -We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$). 6567512 BBS1;11641 BBS7;12395 c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582 Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386 0 -Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged TEK) and GFP-@GENE$ followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-CYP1B1 are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). 5953556 CYP1B1;68035 TEK;397 R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016 I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918 0 -KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, @GENE$-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. 5578023 KCNQ1;85014 KCNH2;201 p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757 p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330 0 -We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, @VARIANT$, in one of the @VARIANT$ carriers (SH107-225) (Figure 4A). She inherited c.235delC of @GENE$ from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). 4998745 MITF;4892 GJB2;2975 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 0 -In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in @GENE$ were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3). Therefore, the inherited @GENE$ variant and de novo TIMP3 variant could contribute to BAVM via additive effects on the same pathway. 6161649 TIMP3;36322 RASA1;2168 c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745 c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293 0 -(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R566L, p.@VARIANT$) vector plasmids and myc-tagged WT or mutant TTC26 (@VARIANT$, p.R50C). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and @GENE$ genes (figure 1). 7279190 FLNB;37480 TTC26;11786 A2282T;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246 p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260 0 -The pathogenicity of the @VARIANT$ mutation in @GENE$ is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (p.T1868del) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention. Three protocadherin-15 isoforms (CD1-3) that differ in their intracytoplasmic regions have been reported. Already two presumably pathogenic mutations (p.M1853L and p.T1868del) have been found in exon 34 that is specific for CD1. Incidentally, the @VARIANT$ mutation was not only involved in USH1, but has also been found, in homozygous state, in a deaf patient presenting with vestibular arreflexia and without retinitis pigmentosa (C. Bonnet, unpublished). The CD2 isoform(s) of @GENE$ make(s) the transient kinociliary links, whereas the protocadherin-15 isoforms that make transient interstereocilia links and the tip-links are still unknown. 3125325 CDH23;11142 protocadherin-15;23401 p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387 p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217 0 -Detection of mutations Screening of the WNT10A, EDA, EDAR, and EDARADD genes was performed by direct sequencing of five PCR fragments for @GENE$, eight PCR fragments for EDA, ten PCR fragments for EDAR, and eight PCR fragments for @GENE$, which cover the entire cDNA including exons and intron-exon junctions of more than 100 base pairs. We compared all primer sequences to the whole-genome assembly in the ENSEMBL database to verify their uniqueness against gene families. Primer sequences are available upon request. Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (p.R171C and @VARIANT$) and two novel EDA mutations (@VARIANT$ and p.I312M) that were identified in this study. 3842385 WNT10A;22525 EDARADD;15430 p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313 p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 0 -Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and c.158-1G>A in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in MYO7A. Another variation, @VARIANT$ in intron 3 of @GENE$, was derived from the proband and his father. 3949687 MYO7A;219 PCDH15;23401 Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351 158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348 0 -A single control also had two mutations, @VARIANT$ in ALS2 and @VARIANT$ in @GENE$. @GENE$ pathogenicity has only been observed in homozygotes, and this individual was heterozygous. 5445258 TARDBP;7221 ALS2;23264 P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513 A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343 0 -We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 GJB3;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$). 3888818 KAL1;55445 TACR3;824 c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012 p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730 0 -In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). 2737700 GJB6;4936 GJB2;2975 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 0 -"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser." 3842385 EDA;1896 WNT10A;22525 T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. 3842385 EDA;1896 WNT10A;22525 c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329 C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955 0 -This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). 6161649 BMP;55955 ENG;92 c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380 p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). 2737700 GJB2;2975 Cx31;7338 N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SOX10;5055 SNAI2;31127 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). 2737700 GJB3;7338 GJB2;2975 G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943 0 -In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in MYO7A and @GENE$, and, all the more, the mutations in the three genes (Figure 2). 3125325 MYO7A;219 USH1G;56113 c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647 c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353 0 -Although the signaling networks between @GENE$ and @GENE$ remain unclear, their common final pathway in regulating potassium ion circulation in the inner ear can be significantly disrupted by the digenic effect of MITF and GJB2 mutations. A subject with Waardenburg syndrome type II (WS2) in a large Chinese population had both MITF and GJB2 mutations in a compound heterozygous state. The profound SNHL in the subject may have been caused by the digenic effect of GJB2 and MITF mutations, although the WS2 phenotype was caused by the MITF mutation. In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in GJB2 and a de novo variant, @VARIANT$ in MITF. 4998745 GJB2;2975 MITF;4892 c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943 p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251 0 -To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). 2737700 GJB2;2975 Cx31;7338 A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313 299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706 0 -In this family, the evidence-based on the genetic and functional findings indicated that the loss-of-function mutation @GENE$-@VARIANT$ was the detrimental variation, and that the gain-of-function variant @GENE$-@VARIANT$ modulated the phenotype. 5426766 CACNA1C;55484 SCN5A;22738 Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963 R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287 1 -Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 SNAI2;31127 SNAI3;8500 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886 0 -Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. 7877624 EDN3;88 SNAI2;31127 c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286 p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366 0 -Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ @VARIANT$, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. 5966321 CELSR1;7665 SCRIB;44228 p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026 p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763 0 -In addition, the @VARIANT$ (p. Gly194Cys) and @VARIANT$ (p. Gly716Val) variants were identified by the software as harmful. In previous studies, the phenotype of the @GENE$ gene was not completely dominant, and most of the variants were inherited from a normal father or mother. However, most of the patients in our study had de novo variants; one patient inherited the variants from his father, while the other patient inherited the variants from her mother. Two female patients had a frameshift variant of the FGFR1 gene, which showed an infantile uterus and ovary. In the group with a nonreproductive phenotype, variants in the FGFR1 gene were found in one patient with cleft lip and palate, which was consistent with the report of a previous study. Another patient presented with a renal cyst and short stature. Therefore, anosmia, sexual dysplasia, irregular tooth alignment, cleft lip and palate, syndactyly, and renal abnormalities were common phenotypes of IHH patients with FGFR1 gene variants. The @GENE$ gene is located on chromosome 8q12.1 and is autosomal dominant, encoding chromosomal helicase DNA-binding protein 7. 8796337 FGFR1;69065 CHD7;19067 c.580G > T;tmVar:c|SUB|G|580|T;HGVS:c.580G>T;VariantGroup:8;CorrespondingGene:3730;RS#:1064796777 c.2147G > T;tmVar:c|SUB|G|2147|T;HGVS:c.2147G>T;VariantGroup:2;CorrespondingGene:2260 0 -Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) . 5587079 DUOX2;9689 DUOX1 and -2;53905;50506 c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905 p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026 0 -In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, FOXC2 variants p.S36S (synonymous) and @VARIANT$ (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and @GENE$-@GENE$ genes. 6338360 FOXC2;21091 AS1;736 p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139 c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394 0 +sentence,pmcid,gene1,gene2,variant1,variant2,label +"(a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of @GENE$ @VARIANT$ mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type @GENE$ (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1 +"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,RASA1;2168,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0 +"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS7;12395,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0 +"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (c.965delA), @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$) genes.",7877624,SNAI2;31127,C2orf74;49849,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,1 +"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,FUS;2521,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0 +"In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,TIMP3;36322,RASA1;2168,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0 +"Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, @GENE$ (TACR3). Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,tachykinin receptor 3;824,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"Altogether, the results suggest that @GENE$ F307S is a loss-of-function mutation in Drosophila. KAT2B @VARIANT$ but not @GENE$ @VARIANT$ causes cardiac defects in Drosophila Since the presence of SRNS and heart defects in family A was the main phenotypic difference from the other families, we looked more specifically into the cardiac and renal system of the fly.",5973622,KAT2B;20834,ADD3;40893,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,0 +"The proband, who had @GENE$ p.(@VARIANT$), p.(Ser127Thr), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1 +"We identified a novel variant in BBS1 patient #10 c.1285dup (@VARIANT$) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic. A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, was identified in patient #3. BBS1, @GENE$ and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of BBS2 and BBS7 lie in this portion. The variant in @GENE$ is noteworthy, since very few Bardet-Biedl cases are reported in the literature.",6567512,BBS2;12122,BBS7;12395,"p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582",c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0 +The @GENE$-p.R583H variant was previously reported to be associated with LQTS; KCNH2-@VARIANT$ is a novel variant; and @GENE$-p.K897T and KCNE1-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in @GENE$, @GENE$, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,DUSP6;55621,ANOS1;55445,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and @GENE$. 3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, @VARIANT$, and p.Asn1075Ser were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively. Particularly, @VARIANT$ and p.Ala754Pro were highly destabilizing, as their DeltaDeltaGs were higher than 1.00 kcal mol-1.",8621929,LRP6;1747,WNT10A;22525,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,0 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"This analysis indicated that the @GENE$ variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0 +"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, @VARIANT$, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1 +"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and @GENE$-@VARIANT$ (p.R583H) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. Primers used for mutagenesis are available upon request. The @GENE$-WT, KCNQ1-WT, and mutant coding sequences were engineered in bicistronic mammalian vectors pIRES2-EGFP (Biosciences-Clontech, Palo Alto, CA, USA).",5578023,KCNQ1;85014,KCNH2;201,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; @VARIANT$, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.112084C>G;tmVar:g|SUB|C|112084|G;HGVS:g.112084C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1 +"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +"Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0 +"Identification of the KCNQ1, @GENE$ and @GENE$ Variants We identified four variants that could influence the length of the QT interval. Variant KCNQ1-c.G1748A results in the non-conservative substitution of arginine with histidine at position 583 (@VARIANT$) located within the C-terminal domain. Since this variant was previously reported in LQTS patients and is rare in the general population (minor allele frequency (MAF) of 0.000016 in the Exome Aggregation Consortium (ExAC) database), it was initially considered a likely pathogenic mutation. Variant KCNH2-c.G323A causes the replacement of a cysteine residue by tyrosine (p.C108Y) within the N-terminal PAS (Per-Arnt-Sim) domain. Since KCNH2-@VARIANT$ had not previously been reported, we considered it to be a variant of uncertain clinical significance.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0 +"21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 @GENE$, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as @GENE$ induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients.",7689793,EBNA1BP2;4969,Calpain-9;38208,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0 +"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0 +" By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous p.A194T mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL. Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of @GENE$. The pathogenic potential of the p.T123N variant is controversial. Three variants of @GENE$ (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (ANK1) identified in SH 94-208).",4998745,GJB2;2975,USH2A;66151,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399,0 +"Among the 8 novel variants, 4 were classified as P (p.C176R and @VARIANT$ in @GENE$, p.T803fs in @GENE$) or LP (@VARIANT$ in DUOX2), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (@VARIANT$) in MFSD8. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (EHMT1 c.1513G > A at a rate of 4.95 x 10-5, MFSD8 c. 353A > G at a rate of 8.24 x 10-6). As stated above, a heterozygous variant in @GENE$ may not result in developmental regression.",7463850,SLC9A6;55971,EHMT1;11698,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0 +"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/@VARIANT$ was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Sequence alterations were detected in the @GENE$ (@VARIANT$), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and DES (rs144901249) genes.",6180278,COL6A3;37917,RYR1;68069,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0 +"In subject 10035, a deleterious variant within the @GENE$ (Chr2) locus was identified in @GENE$ (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,DYT21;100885773,IMP4;68891,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,0 +"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in @GENE$/TGF-beta signalling.",6161649,MAP4K4;7442,BMP;55955,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0 +"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, @VARIANT$; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Ser817Cys;tmVar:p|SUB|S|817|C;HGVS:p.S817C;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Finally, as regards the USH3 patients, biallelic mutations in @GENE$ and monoallelic mutations in @GENE$ or WHRN were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation.",3125325,USH2A;66151,VLGR1;19815,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,0 +"The brother who is homozygous (II.4) for the TNFRSF13B/TACI @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +KCNH2 @VARIANT$ may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A @VARIANT$ reduced the instability index of @GENE$ protein and sodium current.,8739608,Kv11.1;201,Nav1.5;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"However, this genomic @VARIANT$ variant was not seen in the NCBI SNP database or in 372 ethnically-matched controls, arguing against a polymorphism. This patient also was found to have a novel, heterozygous TACR3 nonsense mutation p.Trp275X not seen in 180 controls (Figure 1C; Table 1). @VARIANT$ lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this @GENE$, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, @GENE$, GNRHR, GNRH1, or KISS1R.",3888818,G-protein coupled receptor;3465,KAL1;55445,c.1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,Trp275;tmVar:p|Allele|W|275;VariantGroup:1;CorrespondingGene:6870;RS#:144292455,0 +" Human ADD3 and KAT2B, were subcloned from human full-length cDNA (ADD3: clone IMAGE: 6649991; @GENE$ clone IMAGE: 30333414) into the expression vectors pLentiGIII and PLEX-MCS, respectively. An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and KAT2B. The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. All constructs were verified by sequencing. @GENE$ or KAT2B depleted podocytes were transduced with WT or mutant ADD3 or KAT2B lentiviral particles, respectively.",5973622,KAT2B;20834,ADD3;40893,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0 +"A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant c.1777C > G (p.Leu593Val) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. De novo variants in EHMT1 have been reported in individuals with autism, but developmental regression has not been reported. Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (@VARIANT$) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0 +"However, none of these signs were evident from metabolic work of the patient with @GENE$ @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and NDUFS8 I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ @VARIANT$ variant in MH.",6072915,PHKA1;1981,RYR1;68069,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,0 +"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, @GENE$, and DFNB16, respectively. Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES.",4998745,DFNB3;56504,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"The @VARIANT$ and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. @VARIANT$ is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The G257 and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the @GENE$ trimer. (B) The side view of the EDA trimer. Discussion This is the first study to show that simultaneous WNT10A and EDA mutations could lead to tooth agenesis in the Chinese population. We found that six participants harbored digenic mutations in both @GENE$ and EDA: two of them had isolated oligodontia and the others had syndromic tooth agenesis.",3842385,EDA;1896,WNT10A;22525,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,I312;tmVar:p|Allele|I|312;VariantGroup:7;CorrespondingGene:1896,0 +"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,DFNB1;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +" Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of @GENE$, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3.",4998745,GJB2;2975,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant c.1777C > G (@VARIANT$) in SLC9A6. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. De novo variants in EHMT1 have been reported in individuals with autism, but developmental regression has not been reported. Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.",7463850,EHMT1;11698,SLC9A6;55971,p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502,p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,0 +"(A) The @GENE$ mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0 +RESULTS Molecular genetic testing of the RAS/MAPK pathway revealed a known pathologic heterozygous mutation in exon 12 of @GENE$ (@VARIANT$) and a novel missense variant in @GENE$ (@VARIANT$; Fig. 3).,5101836,PTPN11;2122,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0 +"In this family, the 40-year-old mother with heterozygous loss of both @GENE$ and @GENE$ showed mild myopathy, whereas her 8-year-old daughter with the same genotype had no muscle weakness indicating variable presentation and the possibility of later-onset clinical features. There are multiple other patient cases identified with single pathogenic variant in one recessive gene and another single VUS in a different recessive gene with no other reportable variant. Multigenic inheritance in LGMD. Pathogenic variants identified in more than one LGMD genes in two patients with unusual disease presentation and progression indicating complex inheritance patterns of LGMD. (A) Patient with homozygous variants in both ANO5 and SGCA genes. NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in ANO5 and SGCA genes, respectively.",6292381,ANO5;100071,COL6A2;1392,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in @GENE$ and a de novo variant, p.R341C in @GENE$. DFNB1 as a molecular etiology was excluded from this subject, while digenic inheritance of SNHL can be proposed for this subject because the pathogenic potential of @VARIANT$ was strongly supported by significant conservation of the p.R341 residue among various species and by the absence of this variant among the 666 control chromosomes from normal hearing control subjects.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"The NEK1 @VARIANT$ variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. @GENE$ variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance.",6707335,CCNF;1335,ALS2;23264,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0 +"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, @VARIANT$, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p.S82T;tmVar:p|SUB|S|82|T;HGVS:p.S82T;VariantGroup:111;CorrespondingGene:6012,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Most had C9orf72 repeat expansion combined with another mutation (e.g. VCP R155H or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in TARDBP.",5445258,TARDBP;7221,ALS2;23264,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0 +(b) A sequence chromatogram showing the @GENE$ (@VARIANT$;p.R85C) mutation. (c) A sequence chromatogram showing the @GENE$ (@VARIANT$;p.I436V) mutation.,5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 @VARIANT$, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,PTK7;43672,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0 +"The other novel missense variant, @VARIANT$ (p.W482R), was also strongly considered pathogenic because the residue was highly conserved among various species including zebrafish and Caenorhabditis elegans as indicated by the high GERP score (6.02). This variant was predicted to be ""probably damaging"" by Polyphen2 (http://genetics.bwh.harvard.edu/pph2/) based on in silico analyses. Furthermore, this variant was not detected among the 544 control chromosomes from normal hearing Korean subjects. Similarly, SH170-377 carrying the p.V193E mutation in GJB2 also contained a previously reported homozygous @VARIANT$*36 mutant allele in Myosin XVA (@GENE$) (NM_016239) (Table 1). Although no other causative deafness mutation was detected in the initial analysis of TES data, Sanger sequencing for the low coverage area (<10x) in TES (see Table S2, Supplemental Content, which illustrates regions showing significantly low depth of coverage in TES: OTOF, STRC, and @GENE$) revealed the two known pathogenic STRC mutations as a compound heterozygous configuration in SB175-334 (Table 1).",4998745,MYO15A;56504,OTOA;71803,c.1444T>C;tmVar:c|SUB|T|1444|C;HGVS:c.1444T>C;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956,p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043,0 +"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0 +"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +"Moreover, the MAF of @GENE$-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-p.G38S were much larger (0.187 and 0.352, respectively). KCNH2-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNQ1;85014,KCNE1;3753,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0 +"The @VARIANT$ variant alters an amino acid that is highly conserved among vertebrates (Figure 5). Another candidate variant in @GENE$ (rs7807826) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, p.Arg687*; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,NOS2;55473,Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +" In this study, we identified nine reported gene variants, and we detected 13 novel variants: @VARIANT$(p. Ser509fs) and c.1524del A(p. Ser509fs) variants in the @GENE$ gene; @VARIANT$ and c.306G > C(p. Arg102Ser) variant in the PROK2 gene: c.963dup A (p. Glu322fs), c.1695_1696insT(p. Lys566Ter), c.580G > T(p. Gly194Cys), c.1886 T > C(p. Val629Ala), c.2147G > T(p. Gly716Val), c.1081 + 1del, c.1974_ 1977del (p. Asn659fs), and c.75_ 78del (p. Thr26fs) variants in the @GENE$ gene; and c.875 T > C (p. Ile292Thr) variant in the SEMA3A gene.",8796337,KAl1;55445,FGFR1;69065,c.1525del A;tmVar:c|DEL|1525|A;HGVS:c.1525delA;VariantGroup:13;CorrespondingGene:3730,c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675,0 +"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-TEK E103D and HA-@GENE$ @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"Limb Girdle Muscular Dystrophy due to Digenic Inheritance of @GENE$ and @GENE$ Mutations We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (rs143445685), CAPN3 (@VARIANT$), and DES (@VARIANT$) genes.",6180278,DES;56469,CAPN3;52,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,1 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Similarly, SH170-377 carrying the @VARIANT$ mutation in @GENE$ also contained a previously reported homozygous @VARIANT$*36 mutant allele in Myosin XVA (MYO15A) (NM_016239) (Table 1). Although no other causative deafness mutation was detected in the initial analysis of TES data, Sanger sequencing for the low coverage area (<10x) in TES (see Table S2, Supplemental Content, which illustrates regions showing significantly low depth of coverage in TES: OTOF, STRC, and OTOA) revealed the two known pathogenic @GENE$ mutations as a compound heterozygous configuration in SB175-334 (Table 1).",4998745,GJB2;2975,STRC;15401,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043,0 +"33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (@VARIANT$) and @GENE$: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.R559W;tmVar:p|SUB|R|559|W;HGVS:p.R559W;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,0 +"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), @GENE$ (@VARIANT$), and DES (rs144901249) genes.",6180278,RYR1;68069,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0 +"In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and @VARIANT$ (p.Gln989Leu) in DSCAM (table 2). @GENE$ and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAML1;79549,DSCAM;74393,p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,c.2966A>T;tmVar:c|SUB|A|2966|T;HGVS:c.2966A>T;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0 +"This analysis indicated that the @GENE$ variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (rs144901249), which results in a @VARIANT$ change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,p.Thr219Ile;tmVar:p|SUB|T|219|I;HGVS:p.T219I;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,0 +"A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the @GENE$-@VARIANT$ mutation led to a decreasing L-type calcium current and the protein expression defect.",5426766,SCN5A;22738,CACNA1C;55484,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,1 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in NRXN1 and @GENE$ contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ p.M170I and @GENE$ @VARIANT$ with SETX @VARIANT$ and SETX p.T14I).,4293318,VAPB;36163,TAF15;131088,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +"Three pathogenic or presumably pathogenic mutations in WHRN were detected in three patients including one USH3 patient, specifically, a novel deletion (c.737delC; @VARIANT$), and two novel missense mutations (p.S11R and @VARIANT$) that affect amino acid residues located in the N-terminal Ala/Gly/Ser-rich stretch (aa 9-31) and immediately after the PDZ2 domain, respectively (Tables 2, 3, Figure 1). Notably, these missense mutations only affect the longer whirlin isoform, which is a component of the ankle link molecular complex together with @GENE$ and @GENE$. No mutations in USH3A were detected in our series of USH patients.",3125325,VLGR1;19815,usherin;66151,p.P246fsX13;tmVar:p|FS|P|246||13;HGVS:p.P246fsX13;VariantGroup:276;CorrespondingGene:26821,p.R379W;tmVar:p|SUB|R|379|W;HGVS:p.R379W;VariantGroup:161;CorrespondingGene:25861;RS#:56059137;CA#:136858,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,DVL3;20928,PTK7;43672,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0 +" Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A3;2223,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +" DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0 +"RESULTS Mutations at the gap junction proteins @GENE$ and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"By contrast, @GENE$ variants @VARIANT$ and @VARIANT$ activated the @GENE$ promoter similar to wt.",5893726,GATA4;1551,CYP17;73875,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0 +"Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and KCNQ1-@VARIANT$ (p.R583H) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"An HA tag was added in frame, before the stop codon, to the C terminus of @GENE$ and @GENE$. The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.",5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0 +"The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the @GENE$/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, @VARIANT$) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0 +"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (p.N382S/@VARIANT$) and @GENE$ (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0 +"Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, @VARIANT$), @GENE$ p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,LAMA2;37306,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0 +"The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0 +"Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation. Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2).",6707335,SQSTM1;31202,KIF5A;55861,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +R583H variant was previously reported to be associated with LQTS; @GENE$-p.C108Y is a novel variant; and KCNH2-@VARIANT$ and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%).,5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,1 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0 +"This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and WNT10A mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0 +"The SEMA7A gene variant was predicted as a VUS according to Varsome, whereas the @GENE$ gene variation was classified as benign. The SEMA7A variant [p.(Glu436Lys)] was absent in the 92 exomes of our local database (Supplementary Table 8). The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, DCC, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant p.(Lys205del). The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PLXNA1;56426,SEMA7A;2678,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for @VARIANT$. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by @GENE$ (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, @GENE$, or KISS1R.",3888818,KAL1;55445,GNRH1;641,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with @GENE$ p.I2547T and SETX p.T14I).",4293318,SOD1;392,SETX;41003,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0 +"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the S100A3 protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A13;7523,S100A3;2223,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes. The two mutations were in cis configuration, inherited together on the same chromosome from her father (Figure 1b). The identification of fragment deletions in @GENE$. (a) The PCR quantification results of IID5.",6565573,COL4A4;20071,COL4A5;133559,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0 +"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0 +"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (@VARIANT$, p.G505D). A novel missense mutation was found in DUOXA2 (c.398G>A, @VARIANT$). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, p.H678R and p.S1067L, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,TG;2430,DUOX2;9689,c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,0 +It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.,5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0 +"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"We observed that recombinant @GENE$ and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (@VARIANT$)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0 +"A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene. The GNRHR frameshift mutation was identified in two different families and has not been reported before. It consists of an 11 base-pair deletion (@VARIANT$), and if translated, would be expected to result in a truncated protein due to a premature termination codon (p.Phe313Metfs*3).",5527354,GNRHR;350,PROKR2;16368,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,c.937_947delTTTTTAAACCC;tmVar:c|DEL|937_947|TTTTTAAACCC;HGVS:c.937_947delTTTTTAAACCC;VariantGroup:7;CorrespondingGene:2798,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Structural changes caused by both the p.Pro226Leu and p@VARIANT$ variations were not predicted to be disruptive and core GATA4 structure was not altered. Since the changes were in the DNA interaction sites, it is expected that both @VARIANT$ and pTrp228Cys mutations could have altered binding and activation of some of @GENE$ interaction partners and could also bind to other promoters and potentially change the transcription of several other genes. In fact, we found segregating genetic variants besides GATA4 in cases 2 and 3 using NGS. In one 46,XY DSD subject without CHD, a heterozygote variant in @GENE$ gene was found.",5893726,GATA4;1551,LRP4;17964,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and @VARIANT$) or reported at rare frequencies (p.Gln106Arg, at 0.2%; p.Val134Gly, at 0.0008%; p.Arg262Gln at 0.2%; and PROKR2 @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/@GENE$) heterozygous mutation.",5527354,GNRHR;350,PROKR2;16368,p.Tyr283His;tmVar:p|SUB|Y|283|H;HGVS:p.Y283H;VariantGroup:8;CorrespondingGene:2798;RS#:1237982349,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0 +"Heterozygous missense mutations in CELSR1 gene have previously been reported in a number of NTD patients.38, 39, 40 Two novel and 3 rare @GENE$ missense variants were identified in 5 anencephaly cases (Table 1 and Table S2 in Appendix S3). SCRIB mutations have previously been implicated in human craniorachischisis.40 Three samples carried more than 1 variant within the same gene: sample 01F292 had 2 rare @GENE$ variants (c.739C>A; @VARIANT$), f11-278 had 1 novel (@VARIANT$) and 1 rare (c.5587C>T) variants in CELSR3 and 693F06 had 2 rare missense variants (c.3109G>C; c.824G>A) in NOS2.",5887939,SCRIB;44228,FAT4;14377,c.6607C>T;tmVar:c|SUB|C|6607|T;HGVS:c.6607C>T;VariantGroup:38;CorrespondingGene:79633;RS#:374328795;CA#:3072948,c.8335C>G;tmVar:c|SUB|C|8335|G;HGVS:c.8335C>G;VariantGroup:17;CorrespondingGene:1951,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).,4293318,VAPB;36163,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0 +"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (@VARIANT$), SNAI2 (c.607C>T) and @GENE$ (@VARIANT$) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family.",7877624,C2orf74;49849,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0 +"Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and @GENE$ (@VARIANT$), both sarcomeric genes.",6359299,MYBPC3;215,TNNT2;68050,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0 +"Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in @GENE$ (c.A2107C, @VARIANT$, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3).",5765430,NR5A1;3638,ZFPM2;8008,p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,p.Met703Leu;tmVar:p|SUB|M|703|L;HGVS:p.M703L;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,1 +"Sequence alterations were detected in the @GENE$ (rs144651558), RYR1 (rs143445685), @GENE$ (@VARIANT$), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,CAPN3;52,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0 +"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,1 +"One missense mutation (@VARIANT$) was found in the major subunit of the L-type calcium channel gene @GENE$ by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance.",5426766,CACNA1C;55484,SCN5A;22738,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1 +"This study provides additional evidence that @GENE$ missense variants may contribute to the development of sALS. Missense variants in the NEFH gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients.",6707335,NEK1;14376,GRN;1577,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0 +"A, The pedigree shows the coinheritance of the monoallelic variants which encode @GENE$ @VARIANT$ and MUTYH p.Tyr179Cys in a family affected by colorectal cancer. All spouses were unrelated and unaffected by cancer. Genotypes: MSH6 p.Thr1100Met (T1100M; blue); @GENE$ @VARIANT$ (Y179C; green); -, wild type.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0 +"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23A@VARIANT$/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.1200G>C/+ MAN1B1c.1000C>T/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.1200G>C; MAN1B1@VARIANT$/c.1000C>T (N = 328) 328 (100***) 2 (0.6***) Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0 +"Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the @VARIANT$ mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism.",4470809,OPTN;11085,TBK1;22742,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0 +"DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and @GENE$ mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 2;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or @VARIANT$ (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0 +"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Finally, as regards the USH3 patients, biallelic mutations in USH2A and monoallelic mutations in VLGR1 or @GENE$ were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation.",3125325,WHRN;18739,MYO7A;219,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"No mutations in @GENE$, @GENE$, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (@VARIANT$) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC5A5;37311,TPO;461,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0 +" Molecular Data All three probands carry two heterozygous variants: SQSTM1, @VARIANT$ (p.Pro392Leu), and TIA1, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A.",3125325,MYO7A;219,USH1C;77476,c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); @GENE$-@VARIANT$ and @GENE$-@VARIANT$. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis.",5954460,LAMA5;4060,COL4A5;133559,p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875,p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060,1 +"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and @GENE$-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +" In a second example, we identified a monoallelic change in SRD5A2 (@VARIANT$, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of @GENE$, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014).",5765430,SF1;138518,SRD5A2;37292,c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,0 +"Sanger sequencing was further performed for validation of the identified variants and analysis of their segregation within each family, using corresponding primer sets for @GENE$ and WNT10A. For numbering gDNA and cDNA mutation positions, the subject's sequence variants were compared to human reference sequences NG_016168.2 and NM_002336.3 for LRP6 and NG_012179.1 and NM_025216.3 for @GENE$. 2.3. Prediction of Structural Alterations Caused by LRP6 Mutations To investigate the potential impact of the identified LRP6 missense mutations on protein structure we conducted computational predictions using PremPS, recently developed software that has been shown to outperform currently available methods. For prediction of p.Ser127Thr and p.Met168Arg the PDB (Protein Data Bank) structure of 3S94 was used, which constituted a crystal structure of the human LRP6 extracellular domain (E1E2). On the other hand, 4A0P, the crystal structure of LRP6-E3E4, was employed for prediction of @VARIANT$, p.Ser817Cys, and @VARIANT$. ""A chain"" was selected in all predictions, and mutation specified manually.",8621929,LRP6;1747,WNT10A;22525,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0 +"Immunocomplex of myc-pendrin L117F, @VARIANT$ and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by @GENE$ stimulation.",7067772,EphA2;20929,ephrin-B2;3019,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"Moreover, the presence of other variants (@GENE$-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare @GENE$ missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,CELSR2;1078,FAT4;14377,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +" Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the @VARIANT$ variant of GJB2. The pathogenic potential of the p.T123N variant is controversial. Three variants of USH2A (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,USH2A;66151,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare @GENE$ (GLDC) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (@VARIANT$; p.Val2517Met) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (CELSR1) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3).",5887939,MTHFR;4349,glycine decarboxylase;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.7549G>A;tmVar:c|SUB|G|7549|A;HGVS:c.7549G>A;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,LQT2;201,KCNE2;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,1 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0 +"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) PCCB G407RfrTer14; 3) NUBPL IVS8DC; 4) @GENE$ @VARIANT$. Two additional variants, p. T4823 M in @GENE$ and @VARIANT$ in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,OAT;231,RYR1;68069,"Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942",p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0 +"On the other hand, the WNT10A p.(@VARIANT$) mutation has been shown to cause hypodontia or no tooth agenesis in heterozygous carriers. The mother who passed this mutation had a full set of permanent dentition except for maxillary third molars. However, when combined with the LRP6 mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(@VARIANT$), p.(Ser127Thr), and WNT10A p.(Glu167Gln) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0 +"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and @GENE$ F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"20 The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include @GENE$, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21 @GENE$ promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors.",7689793,RYR3;68151,TRIP6;37757,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-@VARIANT$ and @GENE$-@VARIANT$. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the @GENE$ have been reported in patients with focal segmental glomerulosclerosis.",5954460,COL4A5;133559,LAMA5;4060,p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875,p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060,0 +"Mutagenesis Sequence variants @GENE$-@VARIANT$ (p.C108Y) and KCNQ1-@VARIANT$ (p.R583H) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"Both the aborted foetuses carried the compound heterozygous pathogenic variants, namely @GENE$: @VARIANT$ and PKD1: c.7583A > G (p.Y2528C) from each parent, and these variants were inferred to have contributed to the foetal PKD. 33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the PKD1: c.4343C > T (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (p.R559W) and PKHD1: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.1386-2A > G;tmVar:c|SUB|A|1386-2|G;HGVS:c.1386-2A>G;VariantGroup:41;CorrespondingGene:5310,c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0 +"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2).",6161649,ENG;92,VEGFR2;55639,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,0 +"25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: @VARIANT$, p.Glu274Asp) and the @GENE$ (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS.",7689793,TRIP6;37757,CAPN9;38208,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0 +"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-@GENE$ proteins @VARIANT$ and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ A115P and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered. A genetic cause was sought in a child with combined multiple pituitary hormone deficiencies. The findings implicate a digenic mechanism of inheritance, with a mutation in @GENE$ and in @GENE$. Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland that is characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic or absent posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland.",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, @GENE$, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,SNAI3;8500,LRP4;17964,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +" Quantitation of epistatic interactions of TCF3 and @GENE$ mutations showing a greater net effect than the sum of each individual mutation. Total Serum Ig, clinical score and TNFRSF13B/TACI @VARIANT$ and @GENE$ @VARIANT$ genotype for each family member, as indicated.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T161fsX191;tmVar:p|FS|T|161||191;HGVS:p.T161fsX191;VariantGroup:5;CorrespondingGene:6929,0 +"Genotypes: @GENE$ @VARIANT$ (T1100M; blue); @GENE$ p.Tyr179Cys (@VARIANT$; green); -, wild type.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,Y179C;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0 +"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and @GENE$/TACI @VARIANT$ mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"The four other variants (CELSR1 p.Q2924H, @GENE$ @VARIANT$ and @GENE$ @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,CELSR1;7665,SCRIB;44228,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0 +"Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, @GENE$, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,SEMA7A;2678,DCC;21081,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0 +"(a, b) Compared with wild-type @GENE$, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 @VARIANT$ showed a decreasing trend in molecular weight and increasing instability. However, the prediction of theoretical pI, aliphatic index and GRAVY presented no significant differences. Compared to the Nav1.5 protein properties of wild-type SCN5A, SCN5A p.R1865H slightly increased its molecular weight and aliphatic index but reduced its instability index. Theoretical pI, aliphatic index, and GRAVY were not affected by @GENE$ p.R1865H.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"A rare variant in @GENE$, c.428C>T; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel @GENE$ Variants To study the impact of the three novel missense variants of NR5A1 on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant NR5A1 expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel NR5A1 variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the His24Leu and @VARIANT$ variants when using the reporters for CYP11A1 and HSD17B3 (Figure 2B,C).",7696449,AMH;68060,NR5A1;3638,p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,Cys30Ser;tmVar:p|SUB|C|30|S;HGVS:p.C30S;VariantGroup:5;CorrespondingGene:6662;RS#:1003847603;CA#:293780979,0 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0 +"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), R5143C, C4870F, and @VARIANT$ with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,G805A;tmVar:c|SUB|G|805|A;HGVS:c.805G>A;VariantGroup:14;CorrespondingGene:7399;RS#:587783023;CA#:270788,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,VAPB;36163,FUS;2521,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0 +"This analysis indicated that the CAPN3 variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the DES gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient.",6180278,CAPN3;52,DES;56469,c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,1 +"The proband is heterozygous for the TNFRSF13B/@GENE$ @VARIANT$ mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (@VARIANT$) in the Transcription Factor 3 (@GENE$) gene encoding the E2A transcription factors, present only in the proband and her son.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1 +"SCUBE2 forms a complex with VEGF and @GENE$ and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies.",6161649,VEGFR2;55639,SCUBE2;36383,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +" Molecular Data All three probands carry two heterozygous variants: SQSTM1, @VARIANT$ (p.Pro392Leu), and @GENE$, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The TIA1 variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0 +"The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and HNF4A R80Q. Both mutations are novel and whilst a different mutation, @VARIANT$, has been reported in @GENE$, further evidence to support the pathogenicity of E508K is lacking.",4090307,HNF1A;459,HNF4A;395,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R80W;tmVar:p|SUB|R|80|W;HGVS:p.R80W;VariantGroup:2;CorrespondingGene:3172,0 +" Recently, Gifford et al., identified three missense variants in MKL2 (Gln670His), @GENE$ (@VARIANT$), and @GENE$ (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MYH7;68044,NKX2-5;1482;4824,Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625,Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,DVL3;20928,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0 +"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1 +"Moreover, patients carrying a LAMA4 @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in @GENE$ play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and MYBPC3 (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and @GENE$ (Asn83His), both sarcomeric genes.",6359299,LAMA4;37604,TNNT2;68050,Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,0 +" In the patient with the monoallelic mutation in exon 1 (@VARIANT$), additional studies were carried out to search for further genetic defects. A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene.",5527354,GNRHR;350,PROKR2;16368,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,1 +" Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (@VARIANT$, p.Q1916R) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that Q1916 is highly conserved across mammals (red font). (C) Topology model of the alpha-subunit of LTCC. The localization of the mutation is indicated by a red dot, and polymorphisms are indicated by green dots. (D) A variant (c.3578G>A, @VARIANT$) in SCN5A.",5426766,CACNA1C;55484,SCN5A;22738,c.5747A>G;tmVar:c|SUB|A|5747|G;HGVS:c.5747A>G;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1 +"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare @GENE$ missense variant @VARIANT$ and a novel @GENE$ missense variant c.10147G>A).",5887939,FZD1;20750,FAT4;14377,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0 +"PREX2 activates PI3K signalling via inhibition of phosphatase and tensin homolog (@GENE$), and both germline and mosaic PTEN variants are associated with AVMs. In patient AVM427, the de novo heterozygous missense variant @VARIANT$ (p.Asp1148Tyr) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to @GENE$-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (@VARIANT$), in EGFR (table 1).",6161649,PTEN;265,Smad1;21196,c.3442G>T;tmVar:c|SUB|G|3442|T;HGVS:c.3442G>T;VariantGroup:3;CorrespondingGene:9765,p.Glu631Ter;tmVar:p|SUB|E|631|X;HGVS:p.E631X;VariantGroup:8;RS#:909905659,0 +"This and our previous study reveal a higher than expected by chance frequency of rare @GENE$ and FOXC1 variants in the analysed cohort of PCG patients (6% and 7.5%, respectively), with either experimentally assessed or inferred moderate functional defects. Segregation analysis of these variants, which were present in the heterozygous state, rule out a monogenic inheritance pattern, indicating according to our earlier reports, that these genetic changes might be involved in either oligogenic or complex transmission of the disease. Moreover, the existence of incomplete penetrance, variable expressivity and of a relatively high proportion (close to 20%) of PCG patients with rare heterozygous @GENE$ variants also suggest non-Mendelian PCG transmission in some cases. In these patients, disease outcome might depend on modifier factors (genetic, stochastic and/or environmental), as will be discussed later. Functional impact of the rare variants The two missense FOXC2 variants (p.(H395N) and (@VARIANT$) and one of the PITX2 amino acid substitutions (@VARIANT$) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation.",6338360,FOXC2;21091,CYP1B1;68035,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0 +"Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (@VARIANT$), @GENE$ (rs138172448), and DES (rs144901249) genes.",6180278,COL6A3;37917,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1 +"In patient AVM028, the de novo heterozygous missense variant c.311T>C (@VARIANT$), in the functional inhibition of zinc metalloproteinases (NTR) domain, was identified in TIMP3 (table 1), which encodes a tissue metalloproteinase inhibitor. @GENE$ inhibits VEGF-mediated angiogenesis by blocking VEGF/VEGFR2 binding (figure 3), a function considered independent of metalloproteinase inhibition and unique to TIMP3 compared with other known TIMPs. In patient AVM359, the de novo heterozygous missense variant c.1592G>A (@VARIANT$) was identified in SCUBE2 (table 1), which encodes a membrane-associated multidomain protein. The variant is predicted to affect a conserved site (SIFT=0, PolyPhen2=1, GERP++=5.68, CADD=24.6). SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (p.Cys531Tyr) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies.",6161649,TIMP3;36322,SCUBE2;36383,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0 +"This sequence variant changes a glutamine codon (CAG) to a translation termination codon (TAG) at position 1252 (NP_002327.2:@VARIANT$) and will likely subject the altered transcript to nonsense mediated decay. The mutation is not documented in the Genome Aggregation Database (gnomAD) or the Taiwan BioBank database. In addition, a missense sequence variant in WNT10A (NG_012179.1:g.6853G>A; NM_025216.3:@VARIANT$; NP_079492.2:p.Arg113His) was also identified (Figure S1A). This variant, designated as rs749324327, has a minor allele frequency (MAF) of ~0.0004 in East Asian (EAS) populations and is predicted to be ""benign"", with a PolyPhen-2 score of 0.015. No potential pathogenic mutations were detected in other candidate genes of FTA. Further Sanger sequencing and segregation analysis indicated that the @GENE$ and @GENE$ mutations were both inherited from the father.",8621929,LRP6;1747,WNT10A;22525,p.Gln1252*;tmVar:p|SUB|Q|1252|*;HGVS:p.Q1252*;VariantGroup:15;CorrespondingGene:4040,c.338G>A;tmVar:c|SUB|G|338|A;HGVS:c.338G>A;VariantGroup:3;CorrespondingGene:80326;RS#:749324327;CA#:2113880,1 +"To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic @GENE$ p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EPHA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0 +"Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0 +"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EphA2;20929,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0 +"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,UNC13B;31376,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"The latter individuals were also carriers of the @GENE$ nonsense mutation @VARIANT$. Specifically, the mother and her twin sister were heterozygous for the @GENE$ missense mutation @VARIANT$ and the ABCC6 nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,GNA14;68386,MRPL15;32210,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the @GENE$ gene in fALS and sALS patients, suggesting its role in ALS.",6707335,MATR3;7830,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0 +" Mutation detection in the family (a) Identification of the recurrent nonsense mutation p.R1141X in the @GENE$ gene. Note the heterozygous @VARIANT$ transition substitution at nucleotide position 3421 (arrow). (b, d) Identification of missense mutations p.V255M and @VARIANT$ in the @GENE$ gene.",2900916,ABCC6;55559,GGCX;639,C T;tmVar:c|Allele|CT|;VariantGroup:26;CorrespondingGene:368,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric Cx26/Cx31 connexons. Furthermore, by cotransfection of mCherry-tagged Cx26 and GFP-tagged @GENE$ in human embryonic kidney-293 cells, we demonstrated that the two connexins were able to co-assemble in vitro in the same junction plaque.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare @GENE$ (GLDC) @VARIANT$ missense variant, possibly indicating a compromised FOCM in this patient.",5887939,MTHFR;4349,glycine decarboxylase;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,1 +"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Moderate iodine deficiency in association with double heterozygosity for @GENE$ and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,1 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and @VARIANT$ (c.1051 G > A p.G351R), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,rs2229113;tmVar:rs2229113;VariantGroup:0;CorrespondingGene:3587;RS#:2229113,0 +"In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental @GENE$-@VARIANT$ mutation might be partly compensated by the persistent inward tail INa produced by the @GENE$-@VARIANT$ channel.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Given the reported normal function of pendrin L117F and @GENE$ S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EphA2;20929,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0 +"These phenotypes were specific, since coinjection of nonmutant human RNF216 or @GENE$ mRNA rescued all phenotypes (Fig. 3, and Fig. S4 in the Supplementary Appendix). @GENE$ mRNA encoding @VARIANT$ and OTUD4 mRNA encoding @VARIANT$ were less effective in rescuing the phenotypes induced by double-MO injection (Fig. 3, and Fig. S4 in the Supplementary Appendix), suggesting not only that these mutant alleles encode functionally deficient proteins but also that epistatic interactions between these mutations contribute to the disease phenotype in the index pedigree.",3738065,OTUD4;35370,RNF216;19442,R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,0 +"Notably, not all @GENE$-@VARIANT$ carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by SCN5A-R1193Q variant and sex. As shown in Table 3, all male individuals carrying the CACNA1C-Q1916R mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant @GENE$-@VARIANT$ showed the ERS phenotypes.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0 +"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0 +" Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +" In a second example, we identified a monoallelic change in @GENE$ (c.G680A, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014). Additionally, the @VARIANT$ SRD5A2 change has been previously found to be causative of micropenis, where it was found in compound heterozygosity or homozygosity in three individuals (Sasaki et al., 2003).",5765430,SRD5A2;37292,SF1;138518,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681,0 +"No significant change was observed with HA-TEK @VARIANT$ with GFP-@GENE$ @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2).",5953556,CYP1B1;68035,TEK;397,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +"Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after @GENE$ stimulation while EphA2 and other mutated pendrins were not affected. f Relative amount of cell surface pendrin is shown. Mean +- SEM; one-way ANOVA; **p < 0.01; *p < 0.05; (n = 3). Source data are provided as a Source Data file. Several amino-acid substitutions of pendrin have been identified from Pendred syndrome patients as well as non-syndromic hearing loss patients with EVA. To gain further insight into the relationship between @GENE$ and pendrin, we examined the interaction of pathogenic forms of pendrin with EphA2.",7067772,ephrin-B2;3019,EphA2;20929,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"By contrast, the expression of human @GENE$ and @GENE$, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, F307, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 @VARIANT$). As a negative control, we re-expressed a predicted potentially damaging KAT2B variant (@VARIANT$ corresponding to Gcn5 S478F) found in a homozygous state in a healthy individual from our in-house database.",5973622,KAT2A;41343,KAT2B;20834,F304S;tmVar:p|SUB|F|304|S;HGVS:p.F304S;VariantGroup:6;CorrespondingGene:39431,S502F;tmVar:p|SUB|S|502|F;HGVS:p.S502F;VariantGroup:3;CorrespondingGene:8850;RS#:141445570;CA#:2284662,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"It should be noted that the mother and her twin sister were heterozygous for one of the GGCX missense mutation @VARIANT$ and one ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. The occurrence of digenic inheritance, although rare, is well established (see e.g.,). The chance of a combination of mutations in the @GENE$ and @GENE$ genes is difficult to calculate, since the precise carrier frequency of the mutations in these genes is not known.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,1 +"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 @GENE$, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25 The contribution of the genetic variants, other than @GENE$ and MUTYH, to cancer risk cannot be completely excluded.",7689793,TRIP6;37757,MSH6;149,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0 +"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a). The @GENE$ variant [NM_033056: @VARIANT$; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,USH1G;56113,PCDH15;23401,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,c.3101G > A;tmVar:c|SUB|G|3101|A;HGVS:c.3101G>A;VariantGroup:2;CorrespondingGene:124590,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving @GENE$, @GENE$, DCC, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant @VARIANT$. The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations.",8446458,DUSP6;55621,ANOS1;55445,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0 +"The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the GGCX gene (@VARIANT$) yet did not display any cutaneous findings are not clear. Specifically, while both @GENE$ mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the p.S300F mutation was more pronounced than that of p.V255M.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and @GENE$. The @GENE$ @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.",5973622,KAT2B;20834,ADD3;40893,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0 +"Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, @GENE$ (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,tachykinin receptor 3;824,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,TACR3;824,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0 +GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-@GENE$ @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2).,5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (@GENE$ @VARIANT$ and SCRIB c.3979G>A).",5887939,DVL3;20928,CELSR1;7665,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0 +"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0 +"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0 +"@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"2.3. Functional Consequences of the @GENE$-@VARIANT$ and KCNH2-p.C108Y Variants To investigate the functional consequences of KCNQ1-p.R583H and @GENE$-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0 +" Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0 +"Many of the @GENE$ mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, @VARIANT$, R165W, F191L, and A197S in Cx26 as well as F193C, @VARIANT$ and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (Cx26, @GENE$, and Cx32) suggested that the EC2 and TM4 domains are important to the function of the Cx31 protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear.",2737700,Cx26;2975,Cx31;7338,M163L;tmVar:p|SUB|M|163|L;HGVS:p.M163L;VariantGroup:7;CorrespondingGene:2706;RS#:80338949,S198F;tmVar:p|SUB|S|198|F;HGVS:p.S198F;VariantGroup:14;CorrespondingGene:2705,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"The brother who is homozygous (II.4) for the @GENE$/TACI @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"The @GENE$ @VARIANT$ (p.His596Arg) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"18 , 19 This gene codes for several isoforms, including the ubiquitously expressed p200 @GENE$, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by OGG1. 20 The identified CUX1 (NM_001202543: @VARIANT$, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,CUX1;22551,TRIP6;37757,c.1438A > G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0 +"Exome analysis of the proband's DNA identified a heterozygous C to T transition at Exon 18 of @GENE$ (NG_016168.2:g.139841C>T; NM_002336.3:@VARIANT$) (Figure 1A). This sequence variant changes a glutamine codon (CAG) to a translation termination codon (TAG) at position 1252 (NP_002327.2:p.Gln1252*) and will likely subject the altered transcript to nonsense mediated decay. The mutation is not documented in the Genome Aggregation Database (gnomAD) or the Taiwan BioBank database. In addition, a missense sequence variant in @GENE$ (NG_012179.1:g.6853G>A; NM_025216.3:c.338G>A; NP_079492.2:@VARIANT$) was also identified (Figure S1A).",8621929,LRP6;1747,WNT10A;22525,c.3754C>T;tmVar:c|SUB|C|3754|T;HGVS:c.3754C>T;VariantGroup:4;CorrespondingGene:4040,p.Arg113His;tmVar:p|SUB|R|113|H;HGVS:p.R113H;VariantGroup:3;CorrespondingGene:80326;RS#:749324327;CA#:2113880,1 +"Proband 17 inherited @GENE$ @VARIANT$ and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,CHD7;19067,CCDC88C;18903,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0 +"For example, two variants in proband P15, p. Ala103Val in @GENE$ and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,PROKR2;16368,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first @GENE$ transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, @GENE$ variants @VARIANT$ (synonymous) and c.*38T>G (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-AS1 genes.",6338360,PITX2;55454,FOXC2;21091,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.S36S;tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +@GENE$ @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction. LIMITATIONS Our study was performed only in the statistical field on @GENE$ @VARIANT$ and SCN5A p.R1865H by WES and predisposing genes analyses.,8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"We identified four genetic variants (@GENE$-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +" @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and @GENE$ mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 @VARIANT$ mutations.",7067772,EPHA2;20929,SLC26A4;20132,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0 +"The c.1787A>G (@VARIANT$) mutation of @GENE$ has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The c.317G>C (@VARIANT$) variant of @GENE$, a rare single nucleotide polymorphism (SNP, rs544478083), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), MBD5 (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (@VARIANT$ and rs882709 in @GENE$, and @VARIANT$ in @GENE$).",4293318,SETX;41003,EWSR1;136069,rs3739927;tmVar:rs3739927;VariantGroup:65;CorrespondingGene:23064;RS#:3739927,rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143,0 +"One patient had a novel de novo variant of @GENE$ (c.1524delA, @VARIANT$) and a hot spot variant of @GENE$ (@VARIANT$, p. Trp178Ser) simultaneously.",8796337,KAl1;55445,PROKR2;16368,p. Ser509fs;tmVar:p|FS|S|509||;HGVS:p.S509fsX;VariantGroup:19;CorrespondingGene:3730,c.533G > C;tmVar:c|SUB|G|533|C;HGVS:c.533G>C;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,1 +"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,VPS13C;41188,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: @VARIANT$; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a). The @GENE$ variant [NM_033056: c.3101G > A; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,USH1G;56113,PCDH15;23401,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,c.3101G > A;tmVar:c|SUB|G|3101|A;HGVS:c.3101G>A;VariantGroup:2;CorrespondingGene:124590,0 +"Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3).",5765430,NR5A1;3638,ZFPM2;8008,p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,1 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"He had no mutations in CHD7, FGF8, FGFR1, @GENE$, PROKR2, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) @GENE$ variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352). Since @VARIANT$ was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease.",3888818,PROK2;9268,NELF;10648,Thr478;tmVar:p|Allele|T|478;VariantGroup:0;CorrespondingGene:26012;RS#:121918340,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0 +"(D) @GENE$ missense mutation. Lam, Laminin G domain; GAIN, GPCR-autoproteolysis inducing (GAIN) domain; 7tm_2, 7 transmembrane receptors. (E) @GENE$ missense mutation. MTHFR, methylenetetrahydrofolate reductase One individual (283F06) was heterozygous for a novel missense variant in the catalytic N-terminal domain of the methylenetetrahydrofolate reductase (MTHFR) gene (c.601C>T; @VARIANT$) (Figure 2D), which was predicted to be damaging by all 6 mutation predictors tested (Table 1). This individual was also heterozygous for the common MTHFR @VARIANT$ variant, and also carries a rare glycine decarboxylase (GLDC) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient.",5887939,CELSR1;7665,MTHFR;4349,p.His201Tyr;tmVar:p|SUB|H|201|Y;HGVS:p.H201Y;VariantGroup:15;CorrespondingGene:2068;RS#:756740686,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,0 +"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,1 +"Moreover, the MAF of @GENE$-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and KCNE1-p.G38S were much larger (0.187 and 0.352, respectively). @GENE$-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNQ1;85014,KCNH2;201,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0 +"The genotypes of @GENE$ (NM_001257180.2: @VARIANT$, p.His596Arg) and PDGFRB (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding SLC20A2, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Pedigree and sequence chromatograms of the patient with the @VARIANT$ in MYO7A and c.158-1G>A in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, @VARIANT$ in intron 3 of PCDH15, was derived from the proband and his father.",3949687,PCDH15;23401,MYO7A;219,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0 +" Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus.",4998745,GJB3;7338,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"The c.229C>T (@VARIANT$) variant in @GENE$ and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2. Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking S100A3, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +"(A) In addition to c.235delC in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,MITF;4892,GJB2;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, @GENE$ @VARIANT$ (p.Leu10Met) and @GENE$ @VARIANT$ (p.Arg248Cys).",7463850,GRIN2A;645,PLXNB2;66630,c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903,c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0 +"Mutagenesis Sequence variants @GENE$-@VARIANT$ (p.C108Y) and @GENE$-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,1 +"Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0 +"The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the @GENE$/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in @GENE$, rs143224912 in SETDB1 and @VARIANT$ in @GENE$, and one novel variant in S100A13, were identified.",6637284,ISG20L2;12814,S100A3;2223,rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0 +"Among these four mutations, while the c.503T>G variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0 +"Moreover, the existence of incomplete penetrance, variable expressivity and of a relatively high proportion (close to 20%) of PCG patients with rare heterozygous @GENE$ variants also suggest non-Mendelian PCG transmission in some cases. In these patients, disease outcome might depend on modifier factors (genetic, stochastic and/or environmental), as will be discussed later. Functional impact of the rare variants The two missense FOXC2 variants (p.(H395N) and (p.(C498R)) and one of the PITX2 amino acid substitutions (p.(P179T)) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation. The functional impact of the second PITX2 amino acid substitution, p.(A188T), could not be functionally evaluated due to DNA cloning difficulties. In fact, the two FOXC2 amino acid changes were found to be hypomorphic whereas the @GENE$ amino acid substitution (@VARIANT$) behaved experimentally as a hypermorphic variant. Additional structural and functional analysis indicated that @VARIANT$ alters polypeptide chain conformation and decreases protein stability, which can explain the associated reduced transactivation.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0 +"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"These data also indicate that an alternate pathway is used for quality control of pro-@GENE$ when @GENE$ alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet.",4853519,COL1A1;73874,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the @GENE$ (@GENE$) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the HNF1A gene.",8306687,glucokinase;55440,CGK;55964,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0 +"M2, @GENE$: @VARIANT$. M3, CYP1B1: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"We report digenic variants in @GENE$ and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0 +"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; @VARIANT$), and @GENE$ (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,1 +"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH1G;56113,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"II: 1 carried the digenic heterozygous mutations of KCNH2 @VARIANT$ and SCN5A @VARIANT$. I: 1 and II: 2 were heterozygous for @GENE$ p.R1865H. Except II: 1, other family members did not carry @GENE$ mutation.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0 +"This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same PROKR2 heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in @GENE$, @VARIANT$;p.A604T (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. @GENE$ and PROKR2 are both expressed in the hypothalamus and pituitary, and reduced expression or activity of PROKR2 is implicated in both Kallmann syndrome and PSIS, perhaps because of the important role this signaling pathway plays in endocrine angiogenesis and neuronal migration in this region of the central nervous system.",5505202,FGFR1;69065,Prokineticin 2;9268,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1810G>A;tmVar:c|SUB|G|1810|A;HGVS:c.1810G>A;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644,0 +"The @GENE$ @VARIANT$ (p.His596Arg) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ @VARIANT$ (p.Arg106Pro) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Coimmunoprecipitation analysis indicated an interaction between wild-type @GENE$ and wild-type FLNB, which did not exist between @VARIANT$ @GENE$ and @VARIANT$ OFD1 (figure 3D).",7279190,OFD1;2677,FLNB;37480,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0 +"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Mutations of the residues could affect the function of the human @GENE$ protein. In the case of R171C mutations, the substitution of Cys, a hydroxylic amino acid with a side chain shorter than Arg, might eliminate the electrostatic interaction of R171 with adjacent residues. The mutation G213S is expected to abolish the hydrophobic interaction of G213 with adjacent residues. Sequences of orthologs and predicted 2D structure of human WNT10A protein. (A) The alignment of orthologs of the human WNT10A protein. The R171 and @VARIANT$ residues are represented by arrowheads. (B) The predicted 2D structure of human WNT10A protein. The R171 and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When @VARIANT$ mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of @GENE$ with its receptors.",3842385,WNT10A;22525,EDA;1896,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1 +"For Case 1, a novel missense VUS (variant of unknown significance) variant (c.361C>T; @VARIANT$) in the @GENE$ gene was identified in the patient and his father. A rare variant in @GENE$, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS.",7696449,STAR;297,AMH;68060,p.Arg121Trp;tmVar:p|SUB|R|121|W;HGVS:p.R121W;VariantGroup:7;CorrespondingGene:6770;RS#:34908868;CA#:4715265,p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,0 +"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (@VARIANT$). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2).",3125325,USH2A;66151,MYO7A;219,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0 +"The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/@GENE$ @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), MBD5 (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of @GENE$ (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1 and -2;53905;50506,DUOX1;68136,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0 +"Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB @VARIANT$).",5887939,DVL3;20928,CELSR1;7665,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"(E) The @GENE$ mutation c.466C>T and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and @VARIANT$ in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +" A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1 +"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/@GENE$, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,1 +"Four genes (including @GENE$, ZFHX3, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,AGXT2;12887,TCF4;2407,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0 +"Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic @GENE$ p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EPHA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"(A) Segregation of the @GENE$-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,TOR2A;25260,ATP2A3;69131,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0 +"These results suggest an important role of @GENE$ as an inducer of @GENE$ endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected.",7067772,ephrin-B2;3019,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for CDH23 , 11%-15% for PCDH15 , and for @GENE$ in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor.",3125325,USH1C;77476,USH2A;66151,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in exon 3 of @GENE$ were detected.,3842385,EDA;1896,WNT10A;22525,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1 +"Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A3;2223,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1 +"On the basis of the data collected in this study, we may speculate that the presence of @GENE$-@VARIANT$, together with three KCNE1-p.G38S alleles, could lead to an increased risk of developing cardiac arrhythmias due to the prolongation of the QT interval. Moreover, the overt LQTS phenotype in our family could be caused by the co-expression, in cardiac cells, of KCNH2-p.C108Y and @GENE$-@VARIANT$. The condition of digenic heterozygosity has been associated with a more severe phenotype, a higher risk of life-threatening events, and a reduced efficacy of beta blocking therapy.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0 +"Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation @VARIANT$ in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0 +"In our study, @VARIANT$(p. Arg631*) and @VARIANT$(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and c.1524del A(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of @GENE$ gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function. Prokineticin-2 (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed @GENE$/PROKR2 variants, which was significantly higher than the 9% in the Caucasian population.",8796337,KAl1;55445,PROK2;9268,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,c.1267C > T;tmVar:c|SUB|C|1267|T;HGVS:c.1267C>T;VariantGroup:7;CorrespondingGene:3730,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +" A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,SCRIB;44228,FAT4;14377,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0 +"25 The @GENE$ (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25 The contribution of the genetic variants, other than MSH6 and @GENE$, to cancer risk cannot be completely excluded.",7689793,RYR3;68151,MUTYH;8156,c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0 +"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 @VARIANT$ and @GENE$/TACI C104R mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug KCNE1-WT or 1 mug @GENE$-@VARIANT$ + 1 mug KCNE1-WT) or 3 mug (1.5 mug KCNH2-WT + 1.5 mug @GENE$-@VARIANT$ or 1.5 mug KCNH2-WT + 1.5 mug empty vector) plasmid per dish were used.",5578023,KCNQ1;85014,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1 +"No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the @GENE$ protein, which affected a secondary CYP1B1-binding site.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0 +"33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (@VARIANT$) and PKHD1: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.R559W;tmVar:p|SUB|R|559|W;HGVS:p.R559W;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,1 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0 +"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), RYR1 (rs143445685), @GENE$ (@VARIANT$), and DES (rs144901249) genes.",6180278,COL6A3;37917,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0 +"Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for @GENE$, @GENE$, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with RIPK4.",6726737,EVC;10949,FGF10;3284,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0 +"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,ANG;74385,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0 +"Similarly, the @GENE$-mutated case P05 in our study carried additional variants in @GENE$ (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88C;18903,DCC netrin 1 receptor;21081,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1 +"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins @VARIANT$ and I148T exhibited diminished interaction with wild-type GFP-@GENE$. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(@VARIANT$) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) PKD2 variant.",7224062,PKD2;20104,PKD1;250,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Ser872Gly;tmVar:p|SUB|S|872|G;HGVS:p.S872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061,0 +"The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of PROKR2 were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,DUSP6;55621,SEMA7A;2678,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709,0 +"The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein. However, the two rare FUS variants (Y25C and @VARIANT$) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein. Although the majority of FUS mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging. In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD).",6707335,ubiquilin-2;81830,FUS;2521,P106L;tmVar:p|SUB|P|106|L;HGVS:p.P106L;VariantGroup:7;CorrespondingGene:2521;RS#:374191107;CA#:8023567,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +" In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. @GENE$ mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (p.Gly226Ser) was identified in @GENE$ (table 1).",6161649,N-cadherin;20424,IL17RD;9717,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,0 +"To investigate the effects of one candidate variant on mutant @GENE$ function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father.",5505202,WDR11;41229,PROKR2;16368,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0 +"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0 +"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,PROKR2;16368,EMX1;55799,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0 +"DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"(B) The predicted 2D structure of human @GENE$ protein. The @VARIANT$ and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The @VARIANT$ and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the EDA trimer. (B) The side view of the EDA trimer. Discussion This is the first study to show that simultaneous WNT10A and @GENE$ mutations could lead to tooth agenesis in the Chinese population.",3842385,WNT10A;22525,EDA;1896,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,G257;tmVar:c|Allele|G|257;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS2;12122,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +"In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0 +"In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/@GENE$, while the mother is heterozygous for the @GENE$/@VARIANT$ (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0 +"CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in @GENE$ were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant @VARIANT$ of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. @GENE$ seems to act similarly as CCDC88C through a digenic/oligogenic model to contribute to IHH.",8152424,CCDC88C;18903,CDON;22996,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0 +"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB6;4936,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"We propose that cysteine to arginine change in position 238 of @GENE$ lacks activity to bind DNA reducing the transactivation of AMH critically. By contrast, variants @VARIANT$ and p@VARIANT$ found in cases 2 and 3 did not affect @GENE$ promoter activity.",5893726,GATA4;1551,CYP17;73875,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0 +"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"In the subject III.1, the variant, carried in the heterozygous status, is the c.868 G > T; @VARIANT$, in the @GENE$ (@GENE$) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the HNF1A gene.",8306687,glucokinase;55440,CGK;55964,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0 +"@GENE$ mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +" Cloning and site directed mutagenesis of @GENE$ and @GENE$ variants The FOXC2 variants p.(C498R) (@VARIANT$) and @VARIANT$ were directly amplified and cloned from the genomic DNA of carriers using the following primers, which incorporated the EcoRI or BamHI restriction sites at the 5' end (indicated in bold): FOXC2-Up-EcoRI, 5'-GGGAATTCCGCGCTCTCTCGCTCTCAGG-3' and FOXC2-Dw-BamHI, 5'-GGGGATCCCCGTATTTCGTGCAGTCGTAGG-3'.",6338360,FOXC2;21091,PITX2;55454,rs61753346;tmVar:rs61753346;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in @GENE$ and @GENE$ contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1 +"In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (@GENE$ c.8282C>T and SCRIB @VARIANT$).",5887939,PRICKLE4;22752,CELSR1;7665,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"The genotypes of SLC20A2 (NM_001257180.2: c.1787A>G, @VARIANT$) and @GENE$ (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding PDGFRB, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,TARDBP;7221,FUS;2521,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2).",6161649,ENG;92,BMP;55955,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0 +A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant c.1777C > G (@VARIANT$) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases.,7463850,SLC9A6;55971,EHMT1;11698,p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502,p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,0 +"The variant pair CCDC141 (@VARIANT$)-PROKR2 (@VARIANT$) was classified by ORVAL as true digenic. The contribution of the three missense variants in @GENE$ and @GENE$ genes, which were homozygous in the index case and heterozygous in the asymptomatic cases (Table 2), to the total number of pathogenic digenic combinations did not differ among the three family members (Figure 4).",8446458,IL17RD;9717,PCSK1;379,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,c.868C > T;tmVar:c|SUB|C|868|T;HGVS:c.868C>T;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,0 +"Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EPHA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"20 The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and @GENE$ (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,EBNA1BP2;4969,CAPN9;38208,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0 +One patient (f93-80) had a novel @GENE$ missense variant (@VARIANT$) with a rare @GENE$ missense variant (@VARIANT$).,5887939,PTK7;43672,CELSR2;1078,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,1 +"Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in @GENE$. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles.",3125325,USH2A;66151,USH1G;56113,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0 +"Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 @VARIANT$ gene.",5671988,TCF3;2408,TACI;49320,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas @GENE$ @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +" DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, @VARIANT$ in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A.",3125325,MYO7A;219,USH1C;77476,c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,SPTBN4;11879,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"C2orf74 gene might interact with @GENE$ gene product and give rise to the spectrum of phenotype varying from severe phenotype with complete penetrance to partial features. Conclusion In this study, we analysed a large family segregating Waardenburg syndrome type 2 to identify the underlying genetic defects. Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the MITF gene and a rare heterozygous, missense damaging variant (c.101T>G; @VARIANT$) in the @GENE$ was identified.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0 +"Nevertheless, when it occurs with a defect in @GENE$, which functions in the same pathway, a combination of deficiencies results in a severe disease phenotype. This phenomenon of ""synthetic lethality"" has long been described in genetics and thought to be implicated in the molecular pathogenesis of digenic inheritance in genetic disorders. In this study, we also showed that a second @GENE$ variant in trans might potentially modify the expressivity of a primary ""driver"" mutation. The proband of Family 3 was a compound heterozygote of p.(@VARIANT$) and p.(@VARIANT$) mutations and had fourteen missing teeth, while his father, who carried the p.(Ala754Pro) mutation, exhibited only two.",8621929,WNT10A;22525,LRP6;1747,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,0 +"@GENE$-@VARIANT$ is an unknown variant. The @GENE$-@VARIANT$ variant is currently annotated as a mutation in the Human Gene Mutation Database (HGMD) database, having been identified in other LQTS subjects.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,DVL3;20928,SCRIB;44228,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,MYO7A;219,CDH23;11142,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0 +"The proband's son (III.1) has inherited the @GENE$ @VARIANT$ mutation, but not the @GENE$/TACI @VARIANT$ mutation.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1 +"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"The mutations of KCNH2 @VARIANT$ and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous SCN5A p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a). Except II: 1, other family members without cardiac event or cardiac disease did not carry KCNH2 mutation. Moreover, the conservation analyses demonstrated that the mutant sites of amino acid sequences of @GENE$ and @GENE$ protein were highly conserved (Figure 2).",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"These phenomenon indicate that the mutated SCAP-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated @GENE$ coding protein. @GENE$-c.1103C>T (@VARIANT$) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +" CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of @GENE$ protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction. LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and SCN5A p.R1865H by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 p.307_308del and SCN5A @VARIANT$ increases the risk of the early-onset LQTS and sinoatrial node dysfunction.",8739608,KCNH2;201,Nav1.5;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"The most common mutation was p.R1110Q (DUOX2: @VARIANT$), which was found in 5 patients, accounting for 11% of all the cases. Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A). A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, DUOXA2 and TPO). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes.",7248516,SLC26A4;20132,TPO;461,c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;VariantGroup:12;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0 +"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0 +"a, b Immunoprecipitation of @GENE$ with mutated pendrin. myc-pendrin A372V, @VARIANT$, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by @GENE$ stimulation.",7067772,EphA2;20929,ephrin-B2;3019,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0 +" Missense variants in the @GENE$ gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients.",6707335,NEFH;40755,GRN;1577,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0 +"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0 +"We report digenic variants in @GENE$ and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0 +"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and PKD2 (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly).",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,0 +" Finally, a subject with the heterozygous p.R143W mutation in GJB2 (SH60-136) carried a p.D771N variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES. However, neither @VARIANT$ in GJB2 nor p.D771N in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3). As a result, @GENE$ was excluded for SH60-136. Pedigree and audiograms of SH60 and segregation of variations of GJB2 and WFS1 in this family: two subjects with SNHL, SH60-138 and SH60-142, showed a discrepancy in the GJB2 genotype. Two unaffected subjects, SH60-137 and SH60-139, also carried @VARIANT$ in WFS1.",4998745,WFS1;4380,DFNB1;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0 +"On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, @GENE$-@VARIANT$ and @GENE$-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,1 +One IHH patient had compound heterozygous @GENE$ mutations (@VARIANT$ and c.629-23G>C); and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.629-21C>G;tmVar:c|SUB|C|629-21|G;HGVS:c.629-21C>G;VariantGroup:4;CorrespondingGene:26012;RS#:768001142;CA#:5370502,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Notably, not all @GENE$-Q1916R carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by SCN5A-@VARIANT$ variant and sex. As shown in Table 3, all male individuals carrying the CACNA1C-Q1916R mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant @GENE$-R1193Q showed the ERS phenotypes. The female CACNA1C-Q1916R mutation carriers with SCN5A-R1193Q variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the CACNA1C-@VARIANT$ mutation (IV-4) showed the ER ECG pattern.",5426766,CACNA1C;55484,SCN5A;22738,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0 +" Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (@VARIANT$), and @GENE$, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The TIA1 variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0 +"However, SCN5A @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure. RNA secondary structural prediction. (a, b) Compared with wild-type @GENE$, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of @GENE$ p.R1865H mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"We observed that recombinant TEK and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of @GENE$ (p.E103D)::CYP1B1 (@VARIANT$), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"Most had C9orf72 repeat expansion combined with another mutation (e.g. VCP @VARIANT$ or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, P372R in @GENE$ and @VARIANT$ in TARDBP.",5445258,TARDBP;7221,ALS2;23264,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0 +"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:@VARIANT$; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to @GENE$ in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (@GENE$).",4470809,OPTN;11085,FUS;2521,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.2086G>A;tmVar:c|SUB|G|2086|A;HGVS:c.2086G>A;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0 +"Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the @GENE$ mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus lead to a reduction of structural stability. However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d).",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS. Based on the seemingly normal reproductive phenotype of Sema3a +/- heterozygous mice, we suggest that the monoallelic mutations in SEMA3A are not sufficient to induce the abnormal phenotype in the patients, but contribute to the pathogenesis of KS through synergistic effects with mutant alleles of other disease-associated genes. Accordingly, the other KS patients who carry monoallelic mutations in @GENE$ are also expected to carry at least one pathogenic mutation in another gene (see footnote).",3426548,KAL1;55445,SEMA3A;31358,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,0 +"At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/@GENE$ signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (@VARIANT$) was identified in @GENE$ (table 1).",6161649,Akt;3785,IL17RD;9717,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS6;10318,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +" Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"The results of our study and the @GENE$ study consistently suggested that the rate of oligogenic inheritance of IHH genes varies and maintains at high levels. According to our data, eight patients had at least two IHH gene variants. Two patients carried three variants and one patient even carried four variants. Our data supported ""additive effect"" and ""cumulative mutation burden"" that were proposed in studies related to IHH. For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant.",8152424,PLXNA1;56426,DCAF17;65979,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,LQT2;201,LQT6;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,1 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Phenotype penetrance CACNA1C-@VARIANT$ +/-SCN5A-R1193Q +/- CACNA1C-Q1916R +/-SCN5A-@VARIANT$ -/- CACNA1C-Q1916R -/-@GENE$-R1193Q -/- Male 100% (4/4 cases) 100% (1/1 case) 0 (0/1 cases) II-4, III-1, III-5, IV-3 III-7 III-3 Female 0 (0/4 cases) 100% (1/1 case) 0 (0/4case) II-3, II-6, III-4, IV-1 IV-4 II-5, III-2, III-6, III-8 Dysfunctional electrophysiology and drug intervention in mutated CaV1.2alpha1C To determine the molecular consequences of the CACNA1C-Q1916R mutation, we transfected @GENE$ with the other 2 subunits (CACNB2b and CACNA2D1) forming the LTCC into HEK293T cells and performed whole cell patch-clamp experiments.",5426766,SCN5A;22738,CACNA1C;55484,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0 +"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +" A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +" Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB3;7338,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,CACNA1A;56383,REEP4;11888,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas @GENE$ p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,1 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0 +"33 Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (p.R559W) and PKHD1: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$).",5887939,FZD6;2617,FAT4;14377,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the @GENE$ (CGK) gene; the III.2 subject carried the @VARIANT$; p.Pro291Arg, in the @GENE$ gene.",8306687,glucokinase;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0 +"RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 @VARIANT$ and @GENE$ @VARIANT$).",5887939,DVL3;20928,SCRIB;44228,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Determination of the evolutionary sequence conservation of @GENE$ in different species revealed that the amino acid corresponding to V255 is fully conserved (Fig. 3e). In contrast, the serine at position 300 was less well conserved, several species depicting proline in this position, although the surrounding amino acid sequences were highly conserved. For example, the sequence homology between the human and mouse 23-amino acid sequence segment surrounding the S300 was 95.7 percent (Fig. 3f). Sequencing of the VKORC1 gene did not disclose any pathogenic mutations. Genotype/phenotype correlations A correlation of the clinical findings with the genotypes revealed that the proband and her sister were compound heterozygotes for the two GGCX missense mutations, potentially explaining their hematologic findings. In contrast, the proband's father, brother, her mother, and the mother's twin sister were heterozygous for one of the GGCX mutations only, designating them as carriers without clinical hematologic findings (Fig. 1g). The latter individuals were also carriers of the @GENE$ nonsense mutation p.R1141X. Specifically, the mother and her twin sister were heterozygous for the GGCX missense mutation @VARIANT$ and the ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0 +"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PRICKLE4;22752,FAT4;14377,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0 +"RESULTS Mutations at the gap junction proteins Cx26 and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB6;4936,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Except for the @GENE$ @VARIANT$ variant, all of the variants were classified as uncertain significance of pathogenicity, implying that functional studies should be conducted in the future to provide additional evidence for the pathogenicity of those novel variants in IHH. A total of 24 rare variants were identified in 77.8% (14/18) of the IHH-affected cases in this study. All of those variants were heterozygous, and most were missense and dispersedly distributed in cases, indicating strong complexity and heterogeneity of IHH. PROKR2 had the highest variant frequency (4/18, 22.2%) in our study. Although @GENE$ variant @VARIANT$ has a relatively high allele population frequency (0.002-0.003) in East Asians, It was proven in previous studies to be functional damaging using in vitro functional assays and was enriched in our IHH cohort.",8152424,FGFR1;69065,PROKR2;16368,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:0;CorrespondingGene:128674;RS#:201835496;CA#:270917,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and @VARIANT$ variants are known variants reported by other study groups.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0 +"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (@VARIANT$)::CYP1B1 (p.A115P), TEK (p.Q214P)::@GENE$ (p.E229K), and @GENE$ (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,CYP1B1;68035,TEK;397,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"Circles: females; squares: males; white symbols: not included in the study; white symbols with genotype: unaffected; black symbols: pulmonary fibrosis affected; +: wild-type ""C"" allele of @GENE$/wild-type sequence of S100A13; -: mutant ""T"" allele of S100A3 (@VARIANT$)/4 bp deletion of @GENE$ (@VARIANT$).",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0 +"Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1 +"The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the @GENE$ gene (p.S300F) yet did not display any cutaneous findings are not clear. Specifically, while both GGCX mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the @VARIANT$ mutation was more pronounced than that of p.V255M.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (@GENE$) and connexin 31 (@GENE$) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,1 +" By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,1 +Direct sequence analysis showing the @VARIANT$ mutation (b and g) and wild type (WT) allele (c and h) of GJB2. Direct sequence analysis showing the 299-300delAT mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the @VARIANT$ (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3. Expression of @GENE$ and @GENE$ in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and Cx31 (b).,2737700,Cx31;7338,Cx26;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CACNA1A;56383,DNAH17;72102,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0 +"SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/@GENE$ binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (p.Cys531Tyr) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking @GENE$ activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo. In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions.",6161649,VEGFR2;55639,SMAD1;21196,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0 +"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,GJB6;4936,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,CYP1B1;68035,TEK;397,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"(a) Digenic inheritance of TNFRSF13B (c.310T>C, @VARIANT$ TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and @GENE$/TACI C104R mutations.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, @GENE$ and TPO). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 @GENE$ variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and @VARIANT$ were novel.",7248516,DUOXA2;57037,TSHR;315,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.K618;tmVar:p|Allele|K|618;VariantGroup:4;CorrespondingGene:7253,0 +"These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (@VARIANT$; p.E2135fsX31), and six missense mutations, four of which (p.R1189W, p.R1379P, p.D2639G, and @VARIANT$) had not been previously reported.",3125325,harmonin;77476,CDH23;11142,c.6404_6405delAG;tmVar:c|DEL|6404_6405|AG;HGVS:c.6404_6405delAG;VariantGroup:207;CorrespondingGene:65217,p.R3043W;tmVar:p|SUB|R|3043|W;HGVS:p.R3043W;VariantGroup:141;CorrespondingGene:64072;RS#:375907609;CA#:5546888,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and @GENE$ (c.9921T>G).",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0 +"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, @GENE$ and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2).",3125325,USH1G;56113,MYO7A;219,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1 +"Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A3;2223,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1 +"The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the @GENE$ gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between DYNC1H1 variants and ALS. Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (H398R and @VARIANT$) were detected in the GBE1 gene.",6707335,MATR3;7830,DYNC1H1;1053,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,R166C;tmVar:p|SUB|R|166|C;HGVS:p.R166C;VariantGroup:21;CorrespondingGene:2632;RS#:376546162;CA#:2499951,0 +"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +" DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and @GENE$-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,PRICKLE4;22752,SCRIB;44228,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +" The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0 +"Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in @GENE$ play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYBPC3;215,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0 +" Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0 +"Somatic overgrowth associated with homozygous mutations in both @GENE$ and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ c.1200G>C (@VARIANT$) and MAN1B1 c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family.",4853519,MAN1B1;5230,SEC23A;4642,p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,SCRIB;44228,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,1 +"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; p.Gln235*), and @GENE$ (NM_013254.3:@VARIANT$; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0 +"The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, @GENE$, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,DCC;21081,PROKR2;16368,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0 +"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the @GENE$ protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +"Nevertheless, in vitro studies demonstrated that the @GENE$-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, G38S could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the KCNQ1 and KCNH2 channels. Given the complexity of the LQTS-related genetic background in our family, we functionally characterized only KCNH2-p.C108Y and KCNQ1-@VARIANT$. Our data demonstrate that the activity of KCNH2-p.C108Y was significantly lower than that of the wild type. This variant exerts a dominant-negative effect and shifts the voltage-dependence of activation when co-expressed with KCNH2-WT (Figure 4). Moreover, our data support the hypothesis that this variant, although localized in the PAS domain, which influences protein trafficking, can reach the plasma membrane. Therefore, we may speculate that the functional defect of @GENE$-C108Y could be compromised conductance.",5578023,KCNE1;3753,KCNH2;201,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS7;12395,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively.",8152424,DMXL2;41022,CDON;22996,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0 +"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and @GENE$ (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (FUS). CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of @GENE$ (NM_001008211.1:@VARIANT$; p.Gly538Glufs27).",4470809,TBK1;22742,OPTN;11085,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,c.1243-740_1612+1292delins25;tmVar:c|INDEL|1243-740_1612+1292|25;HGVS:c.1243-740_1612+1292delins25;VariantGroup:37;CorrespondingGene:10133,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for @GENE$ , 11%-15% for PCDH15 , and for @GENE$ in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor.",3125325,CDH23;11142,USH2A;66151,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +GFP-@GENE$ R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-@GENE$ G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,CYP1B1;68035,TEK;397,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0 +"The p.R341 residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages. Digenic inheritances of GJB2/MITF and GJB2/GJB3 (group II). (A) In addition to c.235delC in @GENE$, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3.",4998745,MITF;4892,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +Representative western blot and bar graph showing expression levels of @GENE$ (A) and @GENE$ (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts.,4853519,SEC23A;4642,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0 +"Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel NR5A1 Variants To study the impact of the three novel missense variants of NR5A1 on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant @GENE$ expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel NR5A1 variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the @VARIANT$ and Cys30Ser variants when using the reporters for @GENE$ and HSD17B3 (Figure 2B,C).",7696449,NR5A1;3638,CYP11A1;37347,p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,His24Leu;tmVar:p|SUB|H|24|L;HGVS:p.H24L;VariantGroup:4;CorrespondingGene:6736;RS#:1262320780,0 +"Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,SNAI3;8500,TYRO3;4585,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,1 +"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0 +" Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in SQSTM1 (p.Pro392Leu) and a variant in @GENE$ (@VARIANT$). At the time of this report, only a single prior myopathy case with the same genetic variants has been reported, but the clinical and myopathological features were not illustrated. There are also two further cases of MRV having the same TIA1 variant but a different @GENE$ mutation (@VARIANT$), one of whom was previously reported as having a SQSTM1-MRV.",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),1 +"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (@VARIANT$).",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1 +"Sequencing of the proband's sister's and her aunt's @GENE$ gene revealed the presence of eight heterozygous polymorphisms in the exons 7-19. This finding argues against large allelic deletions at the 5' half of the gene which might not be detectable by the mutation detection strategy employed in our study. Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and VKORC1 genes. The results demonstrated the presence of two missense mutations in @GENE$. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b).",2900916,ABCC6;55559,GGCX;639,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0 +"On the other hand, EphA2 overexpression did not affect localization of @VARIANT$. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both @GENE$ recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G).",3125325,CDH23;11142,MYO7A;219,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0 +"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"Patient 3 was found to harbor a previously reported p.Arg84His variant in @GENE$, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a @VARIANT$ of NR5A1 (Table 3).",5765430,NR5A1;3638,ZFPM2;8008,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516,0 +"N393D <0.001 @VARIANT$ 0.005(D) 0.109 (B) Muscular dystrophy chr7 150648538 CCA - KCNH2 NM_001204798:exon3:c.921_923del:p.307_308del - - - - Short QT syndrome; long QT syndrome chrX 31854929 T A DMD NM_004011:exon21:c.A3083T:@VARIANT$ - - 0.054(T) 0.999 (D) Cardiomyopathy; muscular dystrophy Note: Chr, chromosome; 1000G, 1000 genomes (2015 version); SNP, single nucleotide polymorphism; B, benign; D, damaging; T, tolerated; -, no report; OMIM, Online Mendelian Inheritance in Man. Conservation analyses at the mutant sites of SCN5A and KCNH2 protein. SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and KCNH2 mutations. @GENE$ p.307_308del and @GENE$ p.R1865H of the proband were validated as positive by Sanger sequencing.",8739608,KCNH2;201,SCN5A;22738,rs147301872;tmVar:rs147301872;VariantGroup:2;CorrespondingGene:3908;RS#:147301872,p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757,0 +"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in @GENE$/TGF-beta signalling.",6161649,ENG;92,BMP;55955,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0 +" Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"Two additional variants, @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,RYR1;68069,CACNA1S;37257,p. T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0 +"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"The proband from Family 1 is consistent with the H1 haplotype based on the presence of homozygous genotypes for @VARIANT$ and rs4797 although this is not definitive because the rs10277 and rs1065154 polymorphisms were not covered. The haplotype of the proband from Family 2 could not be determined based on the available genotype data. For Family 3, sequencing data were available for four family members, and we manually reconstructed the haplotype assuming the minimal number of recombinations. The result indicated that Family 3's haplotype was consistent with either the H2 or the H5 haplotype described in the study by Lucas et al.. On the basis of these results, our three families have at least two different haplotypes associated with the SQSTM1 mutation, indicating that this unique phenotype is not a haplotype-specific effect, as well as demonstrating that these families are not remotely related to each other. Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in @GENE$ (p.Pro392Leu) and a variant in @GENE$ (@VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,rs4935;tmVar:rs4935;VariantGroup:9;CorrespondingGene:8878;RS#:4935,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,FGFR1;69065,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), @GENE$: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1 +" In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,0 +"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.@VARIANT$, p.A2282T) vector plasmids and myc-tagged WT or mutant TTC26 (@VARIANT$, p.R50C). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and @GENE$ genes (figure 1).",7279190,FLNB;37480,TTC26;11786,R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0 +"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Sequence alterations were detected in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), @GENE$ (rs138172448), and DES (@VARIANT$) genes.",6180278,RYR1;68069,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0 +"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and @GENE$ (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,1 +"The proband described by Forlani et al. was heterozygous for HNF1A @VARIANT$ and HNF4A R80Q. Both mutations are novel and whilst a different mutation, R80W, has been reported in @GENE$, further evidence to support the pathogenicity of E508K is lacking. The siblings we describe with the HNF1A P291fsinsC and HNF4A R127W mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic. The @GENE$ P291fsinsC (c.872dup) mutation is the most common of all MODY mutations: it results in a frameshift and premature termination codon. There is no doubt over its pathogenicity and both sisters had inherited this mutation from their diabetic father. The HNF4A @VARIANT$ mutation was first described by Furuta et al. in 1997 and is the most common HNF4A mutation, reported in the literature in 15 families from multiple countries. .",4090307,HNF4A;395,HNF1A;459,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0 +We identified a novel variant in the NOD2 gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R). The new @GENE$ missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation.,3975370,IL10RA;1196,NOD2;11156,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0 +"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ @VARIANT$ and @GENE$ @VARIANT$).",5887939,CELSR1;7665,SCRIB;44228,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,1 +"(E) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in @GENE$ and c.511C>T in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G @VARIANT$) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,p. S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0 +"On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant @VARIANT$. The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,DUSP6;55621,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +" CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between @GENE$ and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0 +"This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same @GENE$ heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in @GENE$, c.1810G>A;@VARIANT$ (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome.",5505202,PROKR2;16368,FGFR1;69065,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.A604T;tmVar:p|SUB|A|604|T;HGVS:p.A604T;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644,1 +"Three of the most common known pathogenic variations in two genes (USH2A and RHO) were detected among seven probands, the three commonest variants were @GENE$ c.2802T > G p.Cys934Trp (13%, 3/23), @VARIANT$ (8.7%, 2/23), and RHO c.403C > T c.403C > T (8.7%, 2/23), and all of these were known pathogenic variations. Genotype-phenotype correlations The proband of the family seven detected a compound heterozygous novel mutation in the @GENE$ gene c.1406C > G (p.Ser469Ter) and c.1498C > T (@VARIANT$).",7196472,USH2A;66151,AGBL5;11053,c.8559-2A > G;tmVar:c|SUB|A|8559-2|G;HGVS:c.8559-2A>G;VariantGroup:11;CorrespondingGene:7399;RS#:397518039(Expired),p.Arg500Cys;tmVar:p|SUB|R|500|C;HGVS:p.R500C;VariantGroup:0;CorrespondingGene:60509;RS#:1299838441,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"However, none of these signs were evident from metabolic work of the patient with @GENE$ @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of @GENE$ @VARIANT$ and NDUFS8 I126V variants remain unknown.",6072915,PHKA1;1981,GBE1;129,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,0 +"Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-@VARIANT$, @GENE$-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, @VARIANT$, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of @GENE$ did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-@GENE$ A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,EphA2;20929,pendrin;20132,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"We did not find a mutation in FGFR1 in any of the individuals carrying a mutation in @GENE$ or PROK2, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in @GENE$ exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,PROKR2;16368,KAL1;55445,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"We did not find a mutation in FGFR1 in any of the individuals carrying a mutation in PROKR2 or @GENE$, either. However, one of the patients heterozygous for the @VARIANT$ mutation in @GENE$ (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,PROK2;9268,PROKR2;16368,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0 +"Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type @GENE$, which did not exist between @VARIANT$ FLNB and @VARIANT$ @GENE$ (figure 3D).",7279190,FLNB;37480,OFD1;2677,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0 +"Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ @GENE$R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,MAN1B1;5230,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While TIMP3 blocks VEGF/@GENE$ signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,VEGFR2;55639,RASA1;2168,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0 +" Digenic inheritances of GJB2/@GENE$ and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the @GENE$ locus.",4998745,MITF;4892,DFNB1;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The p.R341 residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of @VARIANT$ in @GENE$ in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages. Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II).",4998745,MITF;4892,GJB2;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +" CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MEOX1;3326,TBX6;3389,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0 +"By contrast, @GENE$ variants @VARIANT$ and @VARIANT$ activated the CYP17 promoter similar to wt. Transcriptional activity of GATA4 variants on the @GENE$ promoter.",5893726,GATA4;1551,CYP17A1;73875,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0 +"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for @GENE$ (Cx26) and @GENE$ (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,connexin 26;2975,connexin 31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1 +"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,MYO7A;219,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0 +"20 The identified @GENE$ (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include @GENE$, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS.",7689793,CUX1;22551,RYR3;68151,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0 +"Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/@GENE$ C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of TACI gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation. Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2). Nonetheless, recent studies proved that KIF5A variants have a role in ALS. According to earlier studies, KIF5A variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings.",6707335,SIGMAR1;39965,KIF5A;55861,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0 +"The brother who is homozygous (II.4) for the TNFRSF13B/@GENE$ @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, @VARIANT$ (c.379C>T) and a heterozygous frameshift mutation in exon 4 of @GENE$, P291fsinsC (@VARIANT$).",4090307,HNF4A;395,HNF1A;459,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,1 +"(a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), @GENE$ p.307_308del showed a decreasing trend in molecular weight and increasing instability. However, the prediction of theoretical pI, aliphatic index and GRAVY presented no significant differences. Compared to the @GENE$ protein properties of wild-type SCN5A, SCN5A @VARIANT$ slightly increased its molecular weight and aliphatic index but reduced its instability index.",8739608,KCNH2;201,Nav1.5;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Functional impact of the rare variants The two missense @GENE$ variants (p.(H395N) and (@VARIANT$) and one of the @GENE$ amino acid substitutions (@VARIANT$) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation.",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +"Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism.",4470809,OPTN;11085,TBK1;22742,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0 +"However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while @GENE$ mutation was only associated with sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +"Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes. ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered. A genetic cause was sought in a child with combined multiple pituitary hormone deficiencies. The findings implicate a digenic mechanism of inheritance, with a mutation in @GENE$ and in @GENE$. Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland that is characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic or absent posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland.",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"He had no mutations in CHD7, FGF8, @GENE$, PROK2, PROKR2, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (@VARIANT$) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease. This @GENE$ deletion was associated with exon 10 skipping, but was not sufficient to cause KS alone.",3888818,FGFR1;69065,NELF;10648,c.1159-14_22del;tmVar:c|DEL|1159-14_22|;HGVS:c.1159-14_22del;VariantGroup:12;CorrespondingGene:26012,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0 +"In this case, haploinsufficiency of the carboxylase activity and reduced @GENE$ functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the ABCC6 gene (@VARIANT$) and the @GENE$ gene (@VARIANT$) yet did not display any cutaneous findings are not clear.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +"The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of @GENE$, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, Q446R, or @VARIANT$ positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of @GENE$ (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms.",7067772,EphA2;20929,pendrin;20132,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,MYOD1;7857,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (@VARIANT$).",3125325,CDH23;11142,USH2A;66151,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0 +" CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in @GENE$ was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,MYOD1;7857,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0 +"This included the variants in @GENE$ (chr6, NM_000426.3:c.380A > G (@VARIANT$); MAF 1.76 x 10-5) and @GENE$ (chr10, NM_0002211:c.1684_1686del (@VARIANT$); MAF 3.871 x 10-5), which affected amino acid residues that were found to be highly conserved across species (Fig. 1).",8474709,LAMA2;37306,LOXL4;12977,p.Thr127Ala;tmVar:p|SUB|T|127|A;HGVS:p.T127A;VariantGroup:0;CorrespondingGene:3908,p.Glu562del;tmVar:p|DEL|562|E;HGVS:p.562delE;VariantGroup:4;CorrespondingGene:84171,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR1;7665,FAT4;14377,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0 +"Specifically, the mother and her twin sister were heterozygous for the @GENE$ missense mutation @VARIANT$ and the ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. However, the proband's younger brother and father were heterozygous carriers of the p.S300F mutation in the GGCX gene while they also carried the p.R1141X mutation in the @GENE$ gene; they did not display any signs of cutaneous findings or hematologic disorder.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with @GENE$ p.I2547T and SETX @VARIANT$).",4293318,ANG;74385,SETX;41003,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0 +"A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous.",5445258,ALS2;23264,TARDBP;7221,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,1 +"The c.229C>T (@VARIANT$) variant in S100A3 and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2. Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +" Mutation detection in the family (a) Identification of the recurrent nonsense mutation @VARIANT$ in the @GENE$ gene. Note the heterozygous C T transition substitution at nucleotide position 3421 (arrow). (b, d) Identification of missense mutations p.V255M and @VARIANT$ in the @GENE$ gene.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +"Pathogenic effects of GBE1 @VARIANT$ and @GENE$ I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the RYR1 p.T4823 M variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with @GENE$ p. R498L, previously reported in a single MHS subject. However, the frequency of this variant in the general population is about 20-fold higher than the frequencies of pathogenic CACNA1S variants associated with MHS. It is also important to note that the diagnostic test for MH has a high false-positive rate of 22%, which raises the possibility that MHS diagnosis in subject R462 may be false. Based on these results, we also ruled out a pathogenic role of the CACNA1S @VARIANT$ variant in MH.",6072915,NDUFS8;1867,CACNA1S;37257,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Two potential disease-causing mutations were identified: (d) ENAM: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) LAMA3 missense mutation c.1559G>A/@VARIANT$. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (@GENE$ and @GENE$) mutations.",6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,1 +" CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in @GENE$ was also identified. Although no direct interaction between @GENE$ and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).",7549550,MYOD1;7857,RIPPLY1;138181,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0 +"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, DUOXA2 and @GENE$). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, p.S309P and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The @GENE$ variant p.R450H was a recurrent inactivating mutation and p.C176R and @VARIANT$ were novel.",7248516,TPO;461,TSHR;315,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,p.K618;tmVar:p|Allele|K|618;VariantGroup:4;CorrespondingGene:7253,0 +"Digenic Inheritance of @GENE$ and @GENE$ Mutations in Patient with Infantile Dilated Cardiomyopathy Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, @VARIANT$) and a known DCM mutation in MYH7 (c.2770G > A; @VARIANT$).",6359299,LAMA4;37604,MYH7;68044,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,1 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I).,4293318,ANG;74385,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0 +"Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature. The three-missense variants were searched for in both parents to check their pattern of inheritance. The mother carried the three variants (@VARIANT$, S159G and G351R) observed in the patient, while the father results heterozygous only for the G351R variant (Figure 1). The new @GENE$ missense variant was searched for in 60 anonymous healthy Italian donors to confirm if it was not a polymorphism, but a true mutation: no variant has been found.",3975370,IL10RA;1196,NOD2;11156,p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0 +"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance.",6707335,CCNF;1335,alsin;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0 +"Most variants were included in the databases or reported in previous studies, except for one heterozygous variant in TSHR (i.e., @VARIANT$) that was novel. Interestingly, we found that variants in the genes causing DH were more common than those in the genes causing TD (87.9% versus 12.1%). We further observed that, among the 58 identified variants, the genes with the most frequent variants were DUOX2 (70.7%), followed by TSHR (12.1%), DUOXA2 (10.3%), and @GENE$ (5.2%) (Figure 1). In addition, seven of these variants were detected in more than one patient: five DUOX2 variants, one DUOXA2 variant, and one @GENE$ variant (Table 2). We found that these variants accounted for 53.4% (31/58) of the total variants, with the @VARIANT$ and p.Arg1110Gln mutations in DUOX2 constituting the predominant sites in the present cohort.",8446595,TPO;461,TSHR;315,p. Ala579Val;tmVar:p|SUB|A|579|V;HGVS:p.A579V;VariantGroup:31;CorrespondingGene:7253,p.Lys530*;tmVar:p|SUB|K|530|*;HGVS:p.K530*;VariantGroup:34;CorrespondingGene:50506,0 +"There is a splicing site mutation c.1339 + 3A>T in @GENE$, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0 +"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +" A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"The changed site (position 307) of @GENE$ p.307_308del was located close to the largest hydrophobic region of the protein (Figure 5a). The hydrophobicity of predicted amino acid residues and adjacent sequences was significantly weakened, which probably made the largest hydrophobic domain (position 303) disorganized. The changed site of the SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant (Figure 5b). Transmembrane structure analysis (Table 4) showed that the mutant site of KCNH2 @VARIANT$ was located in the protein's transmembrane domain, which suggested that the site may be associated with potential functions, including protein localization, substances transportation, ion channels, and others. Phosphorylation analysis of KCNH2 p.307_308del showed that this mutation caused amino acid residues near position 309 dephosphorylation. The result indicated that KCNH2 p.307_308del might impact the catalytic efficiency of protein. However, there was no significant change in protein phosphorylation for @GENE$ @VARIANT$ (Table 4).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the @GENE$ repeat expansion or a missense variant in SOD1 in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,C9ORF72;10137,VAPB;36163,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0 +"However, loss-of-function mutations in @GENE$ have not hitherto been described, and its role in thyroid biology remains undefined. Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a @GENE$ homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred.",5587079,DUOX1;68136,DUOX2;9689,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0 +"In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0 +"The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DMXL2;41022,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,1 +" A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD;8321;8323,FAT4;14377,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0 +"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/Cx31 connexons.",2737700,GJB3;7338,Cx26;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0 +"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, @GENE$, @GENE$, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TG;2430,DUOX2;9689,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0 +"Therefore, in this study, @GENE$ @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD. Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0 +"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,1 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,TARDBP;7221,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0 +"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,0 +"SCAP-c.3035C>T (p.Ala1012Val) variant impaired the negative feedback mechanism of cholesterol synthesize in H293T cell lines @GENE$-c.3035C>T (p.Ala1012Val) variant was introduced into H293T cell lines by CRISPR-Cas9 methodology. After incubated with medium A (as described in the materials and methods section) for 6 hours, the wild-type goups showed a significant different distribution of SREBP-2 in cytoplasm and nucleus, (Figure 4A) while the SCAP-mutated groups shows no such difference (Figure 4B). These phenomenon indicate that the mutated SCAP-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-c.1103C>T (@VARIANT$) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, @GENE$ @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0 +"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CACNA1A;56383,TRPV4;11003,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0 +"On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f).",7067772,EphA2;20929,ephrin-B2;3019,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0 +"DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant @GENE$ allele from his mother; WNT10A mutations in the parents could not be analyzed.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous @GENE$ p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +" Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0 +"On the other hand, @GENE$ overexpression did not affect localization of G672E. The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and @GENE$ S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The @VARIANT$ and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0 +"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,REEP4;11888,VPS13C;41188,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0 +" In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing BMP/TGF-beta signalling.",6161649,MAP4K4;7442,ENG;92,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0 +"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0 +"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Proband 17 inherited @GENE$ p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant.",8152424,CHD7;19067,CDON;22996,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +" Results We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and @GENE$ @VARIANT$ (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter-defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with @GENE$ @VARIANT$ as a de novo mutation, but not existed in other family members.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"R85C in @GENE$ (MIM 607123; NM_144773.2; @VARIANT$) inherited from an unaffected mother and @VARIANT$;p.I436V in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,rs141090506;tmVar:rs141090506;VariantGroup:1;CorrespondingGene:128674;RS#:141090506,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1 +"Her mother with c.1339 + 3A>T in COL4A5 and her father with a missense mutation @VARIANT$ in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A4;20071,COL4A3;68033,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"The other two @GENE$ variants, c.2450C>G (p.Ser817Cys) and @VARIANT$ (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the @GENE$ mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0 +"KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"He also had a @GENE$ deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, @GENE$, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,KAL1;55445,PROK2;9268,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR2;1078,FZD6;2617,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0 +" Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Further molecular studies are needed to prove the deleterious character of the @GENE$ Lys205del variant. Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,PROKR2;16368,SEMA7A;2678,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0 +"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0 +"M, mother; F, father; S1, sister; all unaffected and heterozygous for the @GENE$ @VARIANT$ mutation. Further biochemical evaluation Urine iodine measurements were not available at diagnosis, but subsequent spot measurements suggested mild (P2, 73.9 microg/L) to moderate (P1, 45.6 microg/L) iodine deficiency (RR 100 to 700 microg/L). Moderate iodine deficiency in association with double heterozygosity for DUOX1 and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in MYO7A. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of @GENE$. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of @GENE$. Direct sequence analysis showing the 580G>A (@VARIANT$) mutation (i and n) and WT allele (j and o) of GJB3.,2737700,GJB2;2975,GJB3;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).,4293318,ANG;74385,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0 +"Since @GENE$ localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ @GENE$ and @VARIANT$ OFD1 (figure 3D).",7279190,OFD1;2677,FLNB;37480,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0 +"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH1G;56113,MYO7A;219,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0 +"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be @GENE$, DFNB3, and @GENE$, respectively. Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB7/11;23670,DFNB16;15401,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0 +"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0 +"Most had C9orf72 repeat expansion combined with another mutation (e.g. VCP R155H or @GENE$ @VARIANT$; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in @GENE$ and A90V in TARDBP.",5445258,TARDBP;7221,ALS2;23264,A321V;tmVar:p|SUB|A|321|V;HGVS:p.A321V;VariantGroup:27;CorrespondingGene:23435,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +" Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,ubiquilin-2;81830,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0 +"The synonymous change p.(@VARIANT$) (rs138318843) was carried by four patients (3%), showing a 4- to 10-fold increased frequency compared with that reported in 1000 Genomes and ExAC databases (0.3% and 0.7%, respectively, Table 1). The variant was associated with variable age at diagnosis and IOPs, ranging from two and a half months to three years and from 22 to 45 mmHg, respectively (Table 2). p.(S36S) carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at @GENE$-AS1 intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on FOXC2 and a modifier outcome on both @GENE$ and the overlapping promoter.",6338360,FOXC2;21091,FOXC2-AS1;103752587;2303;5729,S36S;tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +"This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2).",6161649,BMP;55955,ENG;92,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0 +"Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, R127W (@VARIANT$) and a heterozygous frameshift mutation in exon 4 of HNF1A, P291fsinsC (@VARIANT$). @GENE$ therapy was completely discontinued and she was started on glipizide (1.25 mg once daily) with the dose titrated to 2.5 mg once daily based on blood sugar checks, with weekly blood sugar reviews and close support from a diabetes specialist nurse practitioner.",4090307,HNF4A;395,Insulin;173,c.379C>T;tmVar:c|SUB|C|379|T;HGVS:c.379C>T;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,0 +"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +" Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, p.Q1916R) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that @VARIANT$ is highly conserved across mammals (red font). (C) Topology model of the alpha-subunit of LTCC. The localization of the mutation is indicated by a red dot, and polymorphisms are indicated by green dots. (D) A variant (c.3578G>A, @VARIANT$) in SCN5A.",5426766,CACNA1C;55484,SCN5A;22738,Q1916;tmVar:Q1916;VariantGroup:8;CorrespondingGene:775,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0 +"While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane. EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1 +" Results We identified the digenic heterozygous mutations of @GENE$ @VARIANT$ (NM_001204798, c.921_923del) and @GENE$ p.R1865H (NM_001160160, @VARIANT$) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1 +"Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and @GENE$ @VARIANT$, implying that the deleterious variants in @GENE$ act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,FGFR1;69065,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, @GENE$, and BCL9L) as well.",7877624,TYRO3;4585,BCL9;3191,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +" In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in PTPN13 (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0 +"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ @VARIANT$ mutation, but not the TNFRSF13B/TACI C104R mutation.",5671988,TACI;49320,TCF3;2408,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and @VARIANT$; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Based on both clinical and laboratory quantification, it appears neither the TNFRSF13B/@GENE$ @VARIANT$ mutation nor the @GENE$ @VARIANT$ mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1 +"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,TANK-binding kinase 1;22742,OPTN;11085,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0 +"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, @VARIANT$), LAMA2 p.A961T (NM_000426, @VARIANT$), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,KCNH2;201,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug @GENE$-WT or 1 mug KCNQ1-@VARIANT$ + 1 mug KCNE1-WT) or 3 mug (1.5 mug KCNH2-WT + 1.5 mug @GENE$-@VARIANT$ or 1.5 mug KCNH2-WT + 1.5 mug empty vector) plasmid per dish were used.",5578023,KCNE1;3753,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0 +"However, when combined with the @GENE$ mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of LRP6 and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The results showed that, in addition to the @GENE$ gene variant [p.(@VARIANT$)], a second variant in c.2803C > T in the @GENE$ gene was involved in the second highest number of pathogenic digenic combinations (15%), with 18 other variants in 13 genes. The CCDC141 variant was found at a homozygous state in the patient HH1 and at a heterozygous state in the asymptomatic cases. Our analysis indicated that the zygosity state of the @VARIANT$ variant in the CCDC141 gene considerably influenced the rate of pathogenic combinations.",8446458,PROKR2;16368,CCDC141;52149,Pro290Ser;tmVar:p|SUB|P|290|S;HGVS:p.P290S;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,0 +"SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and @GENE$ mutations. KCNH2 @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,UNC13B;31376,MRPL15;32210,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0 +"The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor @GENE$. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation @VARIANT$, but no effect on transactivation activity on the CYP17 promoter for @GENE$ variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only Gly221 and Cys238 are close to Zn binding sites. The Gly221 is not directly involved in Zn binding but is situated next to Cys220 which binds the Zn atom, and therefore, the mutation Gly221Arg will disrupt the Zn binding, leading to a non-functional GATA4. The Cys238 binds Zn and its mutation to arginine leads to loss of Zn binding (Figure 4). GATA4 regulates the expression of multiple genes coding for hormones or components of the steroidogenic pathway during testis development and function. In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development.",5893726,FOG2;8008,GATA4;1551,p.Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"A list of these numerous @GENE$ mutations discovered in patients with CHD so far is provided in Table S2 in Supplementary Material. For a more comprehensive review of the role of GATA4 in CHD we refer to Ref.. By contrast, the few GATA4 missense mutations found in 46,XY DSD individuals with or without CHD are all located in the N-terminal zinc finger domain, which is responsible for DNA binding and interaction with cofactors. Functional characterization of GATA4 variants with respect to the 46,XY DSD phenotype has only been performed for the p.Gly221Arg mutation so far. In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor @GENE$. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the CYP17 promoter for GATA4 variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only @VARIANT$ and @VARIANT$ are close to Zn binding sites.",5893726,GATA4;1551,FOG2;8008,Gly221;tmVar:p|Allele|G|221;VariantGroup:4;RS#:398122402(Expired),Cys238;tmVar:p|Allele|C|238;VariantGroup:0;CorrespondingGene:2626,0 +"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,PTK7;43672,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +Merged images showing pro-@GENE$ colocalization with @GENE$ in wild-type (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double-homozygous (L) fibroblasts.,4853519,COL1A1;73874,TGN38;136490,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, TG, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases. Although dual oxidase 1 (@GENE$) and dual oxidase maturation factor 1 (@GENE$) have established roles in thyroid hormone production, relevant mutations associated with CH have not been found.",6098846,DUOX1;68136,DUOXA1;16043,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in WNT10A (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The LRP6 c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS. It was predicted to be ""possibly damaging"", with a PolyPhen-2 score of 0.767. The WNT10A mutation (c.499G>C, rs148714379), while being rare (MAF = 0.0003), was categorized as a benign variant (PolyPhen-2 score = 0.087). Segregation analysis showed that the father carried the two LRP6 variants, while the mother and the younger sister were both heterozygotes for the @GENE$ mutation. These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and WNT10A.",8621929,WNT10A;22525,LRP6;1747,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0 +"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, DFNB3, and @GENE$, respectively. Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES.",4998745,DFNB16;15401,Wolfram syndrome 1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0 +"These phenomenon indicate that the mutated SCAP-@VARIANT$ (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated @GENE$ coding protein. @GENE$-@VARIANT$ (p.Ala338Val) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG @VARIANT$, and @GENE$ p.T1249I.",4293318,SOD1;392,DCTN1;3011,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,0 +"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; p.Val134Gly, at 0.0008%; @VARIANT$ at 0.2%; and @GENE$ @VARIANT$ at 0.0008%). Discussion The overall prevalence of @GENE$ mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies.",5527354,PROKR2;16368,GNRHR;350,p.Arg262Gln;tmVar:p|SUB|R|262|Q;HGVS:p.R262Q;VariantGroup:5;CorrespondingGene:2798;RS#:104893837;CA#:130198,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0 +"A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in TARDBP. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous. Furthermore, the @GENE$ variant has been previously identified in controls and has unclear status, although it is associated with abnormal localization and aggregation of TARDBP.",5445258,ALS2;23264,TARDBP;7221,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0 +"Four genes (including AGXT2, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-@VARIANT$ (p.Ala1012Val) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +"Genotypes: @GENE$ p.Thr1100Met (@VARIANT$; blue); @GENE$ p.Tyr179Cys (@VARIANT$; green); -, wild type.",7689793,MSH6;149,MUTYH;8156,T1100M;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,Y179C;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"@VARIANT$ carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at @GENE$-AS1 intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on FOXC2 and a modifier outcome on both @GENE$ and the overlapping promoter.",6338360,FOXC2;21091,FOXC2-AS1;103752587;2303;5729,p.(S36S);tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,DVL3;20928,FAT4;14377,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0 +"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 6;4936,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Note that subject II:1 in family PCG-133 was diagnosed at the age of 3 months and carried the de novo @VARIANT$ PITX2 variant, whereas his brother, who did not carry this variant, was diagnosed at the age of 10 years. The proband in family PCG-139 also carried a rare @GENE$ variant (p.(A188T)) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, @GENE$: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,PITX2;55454,CYP1B1;68035,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0 +" Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in @GENE$, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB3;7338,GJB2;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"(D) Validation by Sanger sequencing of the identified @GENE$ @VARIANT$;7117C>T] and @GENE$ @VARIANT$ mutations in the affected individual, the unaffected sibling and her parents.",5967407,RP1L1;105870,C2orf71;19792,c.[326_327insT;tmVar:c|INS|326_327|T;HGVS:c.326_327insT;VariantGroup:0;CorrespondingGene:94137;RS#:771427543;CA#:4625758,c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678,1 +"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, @VARIANT$ (c.100C>T) (rs121908073), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R34X;tmVar:p|SUB|R|34|X;HGVS:p.R34X;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$).,4293318,ANG;74385,VAPB;36163,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0 +"The study revealed @GENE$ gene mutations in a majority of our cohort (33%), in accordance with the percentages already reported in the literature. Interestingly, we found just one patient with variants in BBS1, the most frequently detected gene in BBS patients. We identified a novel variant in BBS1 patient #10 c.1285dup (@VARIANT$) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic. A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, was identified in patient #3. BBS1, BBS2 and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS10;49781,BBS7;12395,"p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582",p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,0 +" In a second example, we identified a monoallelic change in @GENE$ (c.G680A, @VARIANT$, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014).",5765430,SRD5A2;37292,SF1;138518,p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,1 +"@GENE$-@VARIANT$ affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, KCNE1-p.G38S is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the @GENE$-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,PRICKLE4;22752,DVL3;20928,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, p.Tyr27His), MBD5 (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,DNAH17;72102,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0 +"@GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,VEGFR2;55639,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0 +"In our study, we identified four genetic variants in three genes (KCNQ1-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$).",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1 +"We did not find a mutation in @GENE$ in any of the individuals carrying a mutation in @GENE$ or PROK2, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,FGFR1;69065,PROKR2;16368,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0 +"We found eight probands (6.0%) who carried four rare @GENE$ variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare @GENE$ variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, @VARIANT$) have not been previously identified.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0 +" Molecular Data All three probands carry two heterozygous variants: SQSTM1, @VARIANT$ (p.Pro392Leu), and @GENE$, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The TIA1 variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0 +" A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3. @GENE$, BBS2 and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS1;11641,BBS7;12395,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0 +"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +" Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). This mutation was not present in 100 control alleles by restriction enzyme digestion and/or by direct nucleotide sequencing (Fig. 3c). Secondly, a single nucleotide substitution (c.927C T) resulting in substitution of a serine by phenylalanine in position 300 (@VARIANT$) was detected (Fig. 3d).",2900916,GGCX;639,VKORC1;11416,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +" Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES.",4998745,GJB2;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,1 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Two novel @GENE$ frameshift mutations were identified. A single-nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (@VARIANT$/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/@VARIANT$) that cosegregated with both the AI phenotype and the ENAM mutation.",6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,0 +"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,1 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the GGCX gene (@VARIANT$) yet did not display any cutaneous findings are not clear. Specifically, while both GGCX mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the p.S300F mutation was more pronounced than that of p.V255M. In this context, it should be noted that the substrate employed in the carboxylase assay is a pentapeptide, Phe-Leu-Glu-Glu-Leu, and it is possible that the activity measurements if done on full-length @GENE$ as substrate would show differential activity with these two mutant enzymes.",2900916,ABCC6;55559,MGP;693,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +"Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism.",4470809,OPTN;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0 +"Using SIFT and PolyPhen, the @VARIANT$ variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0 +"The large genomic rearrangement in @GENE$ previously reported by Le Guedard et al. was not detected in this group of patients. Three pathogenic or presumably pathogenic mutations in @GENE$ were found in three patients, specifically, an already reported nonsense mutation (@VARIANT$), a novel nucleotide duplication (c.84dupC; @VARIANT$), and a novel sequence variant (c.46C>G; p.L16V).",3125325,PCDH15;23401,USH1G;56113,p.W38X;tmVar:p|SUB|W|38|X;HGVS:p.W38X;VariantGroup:91;CorrespondingGene:124590;RS#:104894652;CA#:252490,p.D29fsX29;tmVar:p|FS|D|29||29;HGVS:p.D29fsX29;VariantGroup:279;CorrespondingGene:26839,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,FGFR1;69065,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Interestingly, it has been reported that the @GENE$-@VARIANT$ variant, located in the PAS domain, reaches the cell surface, but it remains in the immature form and is non-conducting. On the contrary, the functionality of the KCNQ1-p.R583H channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C66G;tmVar:p|SUB|C|66|G;HGVS:p.C66G;VariantGroup:2;CorrespondingGene:3757;RS#:199473416;CA#:6132,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A.",3125325,MYO7A;219,USH1C;77476,c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (c.1823-1G>C), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX2;9689,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0 +"The SLC20A2 c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the PDGFRB c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions. Accordingly, the @GENE$ heterozygous mutation may have played an essential role in promoting the phenotypes of the proband, who showed more extensive brain calcification and headaches significantly ahead of the typical onset age between 30 and 60 years (Wang et al., 2015). To the best of our knowledge, the proband with both @GENE$ and PDGFRB variants in this study is the first reported case resulting from two known pathogenic genes, providing new proof for the digenic effect on clinical heterogeneity among PFBC patients.",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,0 +"Four genes (including AGXT2, ZFHX3, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,TCF4;2407,SCAP;8160,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and @GENE$ c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,CELSR2;1078,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +" Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"On the other hand, EphA2 overexpression did not affect localization of @VARIANT$. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f).",7067772,pendrin;20132,ephrin-B2;3019,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), @GENE$ (c.46C>G; p.L16V) and USH2A (@VARIANT$).",3125325,MYO7A;219,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"To examine whether these mutations affect the ligand-binding specificity of @GENE$ to ephrin-A and ephrin-B, a pull down assay was performed with HEK293T cells due to their low level of endogenous EphA2 expression (Supplementary Fig 7a, b). While tagged versions of EphA2 G355R and EphA2 T511M were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down EphA2 G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 @VARIANT$ and EphA2 T511M with @GENE$ induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d). Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum.",7067772,EphA2;20929,pendrin;20132,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0 +"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b). These EPHA2 mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying c.1300G>A of SLC26A4 was previously reported. She is 22-years-old and presented congenital bilateral sensorineural hearing loss, goitre and skin disorders, while her brother, sister and parents were healthy and did not show such symptoms (Fig. 6a). Another patient carrying @VARIANT$ of SLC26A4 is 14-years-old and exhibited progressive, symmetrical sensorineural hearing loss and goitre (Fig. 6c). Her mother was healthy and carries a mutation of the @GENE$ gene but not the @GENE$ gene (Fig. 6b).",7067772,EPHA2;20929,SLC26A4;20132,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Similarly, reduced expression of @GENE$/E2A has been implicated in equine CVID. There is thus strong support from human, murine and equine studies for the pathogenicity of the TCF3 @VARIANT$ mutation in our family. Our study also offers new insights into the role of TNFRSF13B/TACI mutations in the pathogenesis of CVID. The C104R mutant is a low frequency variant in population databases (0.32% in Exome Aggregation Consortium) and although earlier publications considered this variant to be disease-causing and expressed in up to 10% of CVID patient cohorts, it, and other TNFRSF13B/TACI variants were subsequently found to be present in ~2% of healthy control populations. Although functional studies of C104R mutant alleles have demonstrable defects in B-cell development, switching and differentiation, it is considered a risk allele for CVID, with a relative risk of 4.2 and it has long been speculated that second mutations may be identified in these families. This study is the first demonstration of such digenic inheritance in a CVID-like disorder. In this family, the TNFRSF13B/@GENE$ @VARIANT$ mutation appears to demonstrate a gene dosage effect on serum IgG levels.",5671988,TCF3;100147220,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (@VARIANT$) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0 +"For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (@VARIANT$ or p.R885Q). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (p.R110Q or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, @GENE$, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases. Although @GENE$ (DUOX1) and dual oxidase maturation factor 1 (DUOXA1) have established roles in thyroid hormone production, relevant mutations associated with CH have not been found.",6098846,TG;2430,dual oxidase 1;68136,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-@GENE$ G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, @VARIANT$, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.494C>T;tmVar:c|SUB|C|494|T;HGVS:c.494C>T;VariantGroup:185;CorrespondingGene:4647;RS#:111033174;CA#:278676,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CACNA1A;56383,DNAH17;72102,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0 +"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (@VARIANT$, at 0.2%; p.Val134Gly, at 0.0008%; p.Arg262Gln at 0.2%; and PROKR2 @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/@GENE$) heterozygous mutation.",5527354,GNRHR;350,PROKR2;16368,p.Gln106Arg;tmVar:p|SUB|Q|106|R;HGVS:p.Q106R;VariantGroup:3;CorrespondingGene:2798;RS#:104893836;CA#:130197,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,UNC13B;31376,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and @GENE$/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"@VARIANT$ might affect the normal splicing of exons in the @GENE$ gene, and the novel variant c.306G > C (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the PROKR2 gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (@VARIANT$) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. The hot spot variant c.533G > C (p. Trp178Ser) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity. The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the FGF/@GENE$ signalling pathway.",8796337,PROK2;9268,FGFR1;69065,c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675,p. Arg164Gln;tmVar:p|SUB|R|164|Q;HGVS:p.R164Q;VariantGroup:3;CorrespondingGene:128674;RS#:751875578;CA#:311167332,0 +"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,TRPV4;11003,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of @GENE$ (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary @GENE$-binding site.",5953556,TEK;397,CYP1B1;68035,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340,0 +"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: @VARIANT$, p.Thr1100Met) and MUTYH (NM_001128425.1: c.536A > G, p.Tyr179Cys) genes, while the other 20 genes could not be clearly linked to cancer predisposition. The identified MSH6 variant was classified as a variant of uncertain significance (VUS) in the Leiden Open Variant Database and the InSiGHT DNA Variant Database. 14 , 15 The @GENE$ variant is the most common pathogenic variant found in the Netherlands. 2 The digenic inheritance of MSH6 and MUTYH variants. A, The pedigree shows the coinheritance of the monoallelic variants which encode @GENE$ p.Thr1100Met and MUTYH @VARIANT$ in a family affected by colorectal cancer.",7689793,MUTYH;8156,MSH6;149,c.3299C > T;tmVar:c|SUB|C|3299|T;HGVS:c.3299C>T;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0 + Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1 +@GENE$ @VARIANT$ and @GENE$ @VARIANT$ of the proband were validated as positive by Sanger sequencing.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,0 +" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0 +"Sequence alterations were detected in the @GENE$ (@VARIANT$), @GENE$ (rs143445685), CAPN3 (rs138172448), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,RYR1;68069,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,0 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0 +"Limb Girdle Muscular Dystrophy due to Digenic Inheritance of @GENE$ and @GENE$ Mutations We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (@VARIANT$), RYR1 (rs143445685), CAPN3 (@VARIANT$), and DES (rs144901249) genes.",6180278,DES;56469,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, @VARIANT$), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; rs7673715) c.1226A>G; @VARIANT$ and @GENE$ (MIM 600509; NM_000352.4; rs151344623) @VARIANT$ mutations.,5505202,GBA;68040,ABCC8;68048,p.N409S;tmVar:p|SUB|N|409|S;HGVS:p.N409S;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767,c.3989-9G>A;tmVar:c|SUB|G|3989-9|A;HGVS:c.3989-9G>A;VariantGroup:4;CorrespondingGene:6833;RS#:151344623;CA#:233276,1 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +" Digenic inheritances of GJB2/@GENE$ and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus.",4998745,MITF;4892,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. The @GENE$ p.(Asn1075Ser) mutation substitutes highly-conserved asparagine with serine, which is predicted to destabilize the protein structure.",8621929,WNT10A;22525,LRP6;1747,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0 +"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ @GENE$R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,MAN1B1;5230,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0 +"Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,ATP2A3;69131,MRPL15;32210,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0 +The @VARIANT$ (p.R77C) variant in @GENE$ and @VARIANT$ (p.I80Gfs*13) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.,6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1 +"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ FLNB and p.Y437F @GENE$ (figure 3D). FLNB and OFD1 variants in individuals with AIS. (A) Pedigree of AIS twins. Case 98-73 (proband) is indicated with an arrow. (B) Protein sequences around @GENE$. p.R2003 in 11 species. (C) Local view of in silico structure analysis of the WT and mutant FLNB structures (variant H2003). The WT structure of FLNB is shown in purple, and the mutant structure of FLNB is shown in green. The side chains of R/H2003 are shown as sticks, and the other residues are shown as lines. (D) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R2003H) vector plasmids and myc-tagged WT or mutant OFD1 (@VARIANT$).",7279190,OFD1;2677,FLNB;37480,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0 +"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0 +"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and @GENE$, respectively.",5953556,CYP1B1;68035,TEK;397,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0 +"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), RYR1 (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (rs144901249) genes.",6180278,COL6A3;37917,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0 +"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and @VARIANT$ in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in MYO7A.",3949687,MYO7A;219,PCDH15;23401,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +" Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and @GENE$ mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,SCRIB;44228,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0 +"Five subjects (R279, R410, R465, R469 and R470) carried pathogenic and deleterious variants in genes known to affect glycogen metabolism (GBE1, PYGM), FAO (@GENE$ and CPT2), fatty acid and amino acid catabolism (PCCB), oxidative phosphorylation (ELAC2, NDUFA6, NDUFA10 and NUBPL), mitochondrial matrix enzymes (OAT and TIMM50). Two subjects (R302 and R462) had variants in genes involved in Ca 2+ regulation (@GENE$ and CACNA1S), glycogen metabolism (GBE1 and PHKA1) and oxidative phosphorylation (NDUFS8). Mutations in PHKA1 cause Glycogen Storage Disease type IX, X-linked phosphorylase kinase (PHK) enzyme deficiency, characterized by high muscle glycogen content and severe reduction of muscle PHK activity. However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and NDUFS8 @VARIANT$ variants remain unknown.",6072915,ACADVL;5,RYR1;68069,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0 +"We report digenic variants in @GENE$ and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in ZFPM2 (c.A2107C, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3).",5765430,NR5A1;3638,SRD5A2;37292,p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A).",5887939,PRICKLE4;22752,DVL3;20928,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,0 +Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of @GENE$. Direct sequence analysis showing the 497A>G (@VARIANT$) mutation (d) and WT allele (e) of @GENE$. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.,2737700,GJB2;2975,GJB3;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"These results suggest an important role of @GENE$ as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin @VARIANT$, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated @GENE$ triggered by ephrin-B2 stimulation.",7067772,ephrin-B2;3019,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Under the assumption of an autosomal recessive inheritance pattern, two variants were identified in @GENE$ (c.326_327insT, p.(Lys111Glnfs*27) and c.7117C>T, @VARIANT$) (Table 1, S3 Fig.). Segregation analysis showed that they were both present on the maternal allele (Figs. 1C-D). By analyzing for the presence of variants in genes implicated in intellectual disability, hearing impairment and inherited retinal disease, a heterozygous stop mutation in @GENE$ (@VARIANT$, p.(Ser512*)), a gene previously shown to be involved in autosomal recessive RP.",5967407,RP1L1;105870,C2orf71;19792,p.(Gln2373*);tmVar:p|SUB|Q|2373|*;HGVS:p.Q2373*;VariantGroup:4;CorrespondingGene:94137,c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678,1 +"Four potential pathogenic variants, including @GENE$ @VARIANT$ (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), @GENE$ @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited @GENE$ T168fsX191 and @GENE$/TACI @VARIANT$ mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"Another candidate variant in @GENE$ (rs7807826) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,NOS2;55473,c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,0 +"Some patients exhibited olfactory dysosmia and obesity, which was consistent with the clinical manifestations of extreme obesity in patients with @GENE$ variants reported in previous studies. Two novel variants of the @GENE$ gene were found in patients with anosmia, obvious small phallus, and low levels of sex hormones. c.223 - 4C > A might affect the normal splicing of exons in the PROK2 gene, and the novel variant @VARIANT$ (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the PROKR2 gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (@VARIANT$) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors.",8796337,PROKR2;16368,PROK2;9268,c.306G > C;tmVar:c|SUB|G|306|C;HGVS:c.306G>C;VariantGroup:27;CorrespondingGene:60675,p. Arg164Gln;tmVar:p|SUB|R|164|Q;HGVS:p.R164Q;VariantGroup:3;CorrespondingGene:128674;RS#:751875578;CA#:311167332,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (c.1514G>A, p.G505D). A novel missense mutation was found in @GENE$ (c.398G>A, @VARIANT$).",6098846,TG;2430,DUOXA2;57037,c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,1 +"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1 +"We also identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a @VARIANT$ of @GENE$ (Table 3).",5765430,SRD5A2;37292,NR5A1;3638,c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442,single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516,1 +"DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in @GENE$, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both SEC23A and @GENE$, consistent with an autosomal-recessive mode of inheritance.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0 +"@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-@VARIANT$, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ p.P642R, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, @VARIANT$ and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,PTK7;43672,SCRIB;44228,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,0 +"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (c.965delA), SNAI2 (@VARIANT$) and @GENE$ (@VARIANT$) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family.",7877624,C2orf74;49849,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0 +"One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD;8321;8323,FAT4;14377,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in @GENE$, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both SEC23A and MAN1B1, consistent with an autosomal-recessive mode of inheritance. We also identified heterozygous mutation in @GENE$ in an unaffected sibling of tall stature and normal intelligence.",4853519,MAN1B1;5230,SEC23A;4642,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0 +"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,TARDBP;7221,TAF15;131088,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,CELSR1;7665,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,0 +"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), @GENE$ @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,LAMA2;37306,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and @VARIANT$ (R284C) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation. His mother, a 40-year-old female with one pathogenic variant each in @GENE$ and @GENE$ shows unspecified myopathy with elevated creatine phosphokinase (CPK).",6292381,ANO5;100071,COL6A2;1392,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0 +"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,USH2A;66151,CDH23;11142,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,CAPN11;21392,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"PKD1 sequencing identified a likely pathogenic variant, p.(@VARIANT$), absent in parents, and a second maternally inherited variant, p.(@VARIANT$). This is extremely rare (never reported before, absent in GnomAD), but with benign computational predictions, and it was classified as hypomorphic. We cannot formally test if variants in these two patients are in trans, but we presume they contributed to the severe clinical expression. In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1).",7224062,PKD1;250,PKD2;20104,Asn2167Asp;tmVar:p|SUB|N|2167|D;HGVS:p.N2167D;VariantGroup:33;CorrespondingGene:5310,Ala561Val;tmVar:p|SUB|A|561|V;HGVS:p.A561V;VariantGroup:10;CorrespondingGene:5311;RS#:542353495,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; @VARIANT$) and @GENE$ (@VARIANT$).",3125325,USH1G;56113,USH2A;66151,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,1 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,CELSR1;7665,SCRIB;44228,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +" A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"(A) Segregation of the @GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-@VARIANT$, and @GENE$-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 @VARIANT$, rs761703397), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0 +"Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,1 +"Novel Missense Mutation in the @GENE$ Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association? Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.@VARIANT$ p.K953E) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R).",3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-@GENE$. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare glycine decarboxylase (@GENE$) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (@VARIANT$; p.Val2517Met) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (CELSR1) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3).",5887939,MTHFR;4349,GLDC;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.7549G>A;tmVar:c|SUB|G|7549|A;HGVS:c.7549G>A;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383,0 +"Six variants in PKD1 occurred de-novo, three of which were not previously described: @VARIANT$.(Asp1079Alafs*25), c.8860G>T p.(Glu2954*), and c.9201+1G>A. One de-novo and novel variant was also detected in PKD2: c.992G>A p.(@VARIANT$). Types of 158 distinct possible pathogenic variants detected in @GENE$ and @GENE$ genes.",7224062,PKD1;250,PKD2;20104,c.3236del p;tmVar:c|DEL|3236|P;HGVS:c.3236delP;VariantGroup:47;CorrespondingGene:5310,Cys331Tyr;tmVar:p|SUB|C|331|Y;HGVS:p.C331Y;VariantGroup:1;CorrespondingGene:23193;RS#:144118755,0 +"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,0 +"This analysis indicated that the @GENE$ variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (rs144901249), which results in a @VARIANT$ change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,p.Thr219Ile;tmVar:p|SUB|T|219|I;HGVS:p.T219I;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,0 +"The heterozygous SCN5A@VARIANT$ was carried by her father and sister but not carried by I:2. II:1 carried with @GENE$ @VARIANT$ as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index. Conclusions The digenic heterozygous KCNH2 and @GENE$ mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the @GENE$/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a @GENE$ (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,WDR11;41229,EMX1;55799,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0 +" A new pathogenic variant in @GENE$ affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, was identified in patient #3.",6567512,BBS2;12122,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0 +"Mutations in @GENE$ (MITF), coding for a basic helix-loop-helix (BHLH) leucine zipper protein, are known to cause the WS2 phenotype due to defects in survival, proliferation, and migration of melanocytes. The deletion mutation (@VARIANT$) identified in this study lies in the BHLH domain and predicted to cause frameshift (p.Asn322fs) and stop codon seven amino acids downstream (Asn322Metfs*7). The missense variant (c.101T>G) in the C2orf74 gene changes the conserved amino acid Valine to Glycine (@VARIANT$). C2orf74 is an uncharacterized gene and no functional data is available, however, Expression Atlas detected the expression of the gene in the eye (https://www.ebi.ac.uk/gxa/home). The gene @GENE$ is present in the genomic region shared by all affected individuals and therefore, we consider this as a candidate gene for WS2 phenotype.",7877624,melanocyte inducing transcription factor;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0 +"According to earlier studies, @GENE$ variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS.",6707335,KIF5A;55861,SPG11;41614,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0 +"The presence of concomitant mutations, such as the TCF3 @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0 +"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric Cx26/Cx31 connexons. Furthermore, by cotransfection of mCherry-tagged @GENE$ and GFP-tagged Cx31 in human embryonic kidney-293 cells, we demonstrated that the two connexins were able to co-assemble in vitro in the same junction plaque.",2737700,GJB6;4936,Cx26;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d).",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and @GENE$ were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2).",3125325,USH2A;66151,MYO7A;219,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0 +"However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,CCDC88C;18903,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0 +"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (@VARIANT$), SNAI2 (c.607C>T) and C2orf74 (@VARIANT$) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); @GENE$ M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,SEC23A;4642,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with @GENE$/@GENE$ mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0 +"a, b Immunoprecipitation of EphA2 with mutated @GENE$. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by ephrin-B2 stimulation.",7067772,pendrin;20132,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: @VARIANT$ and p.(H395N); @GENE$: @VARIANT$).,6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GENE$ p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and @VARIANT$ was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,DVL3;20928,CELSR1;7665,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0 +"Therefore, this amino acid replacement may affect protein interactions taking place in the transcriptional inhibitory domain where it is located, leading to increased @GENE$ activity. In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, FOXC2 variants p.S36S (synonymous) and @VARIANT$ (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-@GENE$ genes.",6338360,PITX2;55454,AS1;736,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394,0 +"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0 +"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, @VARIANT$, p.S82T, p. A85P, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p.P79T;tmVar:p|SUB|P|79|T;HGVS:p.P79T;VariantGroup:108;CorrespondingGene:6012,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,0 +"Moreover, the existence of incomplete penetrance, variable expressivity and of a relatively high proportion (close to 20%) of PCG patients with rare heterozygous @GENE$ variants also suggest non-Mendelian PCG transmission in some cases. In these patients, disease outcome might depend on modifier factors (genetic, stochastic and/or environmental), as will be discussed later. Functional impact of the rare variants The two missense FOXC2 variants (@VARIANT$ and (p.(C498R)) and one of the @GENE$ amino acid substitutions (p.(P179T)) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation. The functional impact of the second PITX2 amino acid substitution, p.(A188T), could not be functionally evaluated due to DNA cloning difficulties. In fact, the two FOXC2 amino acid changes were found to be hypomorphic whereas the PITX2 amino acid substitution (@VARIANT$) behaved experimentally as a hypermorphic variant.",6338360,CYP1B1;68035,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/@GENE$ signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,TIMP3;36322,VEGFR2;55639,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0 +"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD. Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G @VARIANT$) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,p. S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"In addition, we have confirmed that immunoreactive signal corresponding to the anti-ephrin-B2 antibody was colocalized with that to the anti-@GENE$ antibody in the inner ear (Supplementary Fig. 3g). These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of @GENE$ are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, @VARIANT$ were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected.",7067772,EphA2;20929,pendrin;20132,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"Patient 3 was found to harbor a previously reported p.Arg84His variant in @GENE$, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, @VARIANT$:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3).",5765430,NR5A1;3638,ZFPM2;8008,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,rs9332964;tmVar:rs9332964;VariantGroup:0;CorrespondingGene:6716;RS#:9332964,0 +"Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation @VARIANT$ in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A4;20071,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0 +"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. @GENE$ gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database).",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0 +"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,SPTBN4;11879,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,CDON;22996,DCC;21081,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0 +"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB6;4936,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"A single @GENE$ mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; @VARIANT$, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (WNT10A c.637G>A, @VARIANT$) in EAS.",8621929,WNT10A;22525,LRP6;1747,g.146466A>G;tmVar:g|SUB|A|146466|G;HGVS:g.146466A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$).",5887939,DVL3;20928,SCRIB;44228,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1 +"Finally, as regards the USH3 patients, biallelic mutations in USH2A and monoallelic mutations in @GENE$ or @GENE$ were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation.",3125325,VLGR1;19815,WHRN;18739,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (@GENE$ c.8282C>T and @GENE$ @VARIANT$).",5887939,CELSR1;7665,SCRIB;44228,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,HS1BP3;10980,GNA14;68386,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,1 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0 +"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0 +"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, @VARIANT$ (c.100C>T) (rs121908073), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R34X;tmVar:p|SUB|R|34|X;HGVS:p.R34X;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; @VARIANT$, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,g.124339A>G;tmVar:g|SUB|A|124339|G;HGVS:g.124339A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0 +"Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense @GENE$ variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,PTPN11;2122,SOS1;4117,c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,1 +"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis. We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: 179264731T/C, rs10277; Ch5: 179264915G/T, @VARIANT$ ].",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,rs1065154;tmVar:rs1065154;VariantGroup:2;CorrespondingGene:8878;RS#:1065154,0 +"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0 +"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,DUSP6;55621,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0 +"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, rs147680216) in EAS. The novel LRP6 c.503T>G mutation substitutes the hydrophobic methionine168 for an arginine (p.Met168Arg) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1. The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and @VARIANT$ (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. @GENE$ @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,USH2A;66151,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Sequence alterations were detected in the @GENE$ (rs144651558), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,RYR1;68069,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0 +"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0 +"The side chains of R/L566 and @VARIANT$ are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C).",7279190,FLNB;37480,TTC26;11786,A/T2282;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0 +"Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (@VARIANT$)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0 +"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, @VARIANT$ and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of @GENE$ (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,PTK7;43672,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,0 +"The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, DCC, PROP1, PLXNA1, and @GENE$ genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,SEMA7A;2678,PROKR2;16368,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0 +" The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0 +" Molecular Data All three probands carry two heterozygous variants: @GENE$, @VARIANT$ (p.Pro392Leu), and @GENE$, c.1070A>G (@VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1 +"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including @GENE$ may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, LRP5, @GENE$, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,LEF-1;7813,LRP6;1747,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,TARDBP;7221,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0 +"A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, @VARIANT$, was identified in patient #3. BBS1, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of @GENE$ and @GENE$ lie in this portion.",6567512,BBS2;12122,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of @GENE$ (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1 and -2;53905;50506,DUOX1;68136,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0 +" Finally, a subject with the heterozygous p.R143W mutation in GJB2 (SH60-136) carried a p.D771N variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES. However, neither @VARIANT$ in @GENE$ nor @VARIANT$ in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,WFS1;4380,GJB2;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0 +"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI @VARIANT$ mutations. Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +" In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in @GENE$ (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating @GENE$ signalling. In addition to Smad1-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (p.Glu631Ter), in EGFR (table 1). Oncogenic EGFR stimulates angiogenesis via the VEGF pathway. As a truncated germline EGFR variant has not been reported in humans, c.1891G>T (@VARIANT$) in patient AVM312 was classified as likely pathogenic and EGFR as a candidate gene due to the vital role of EGFR in EGF and VEGF signalling.",6161649,ZFYVE16;8826,BMP;55955,p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765,p.Glu631Ter;tmVar:p|SUB|E|631|X;HGVS:p.E631X;VariantGroup:8;RS#:909905659,0 +" Tumor analysis MMR deficiency in tumor samples was assessed by microsatellite instability analysis and immunohistochemical detection of the four MMR proteins (MLH1, MSH2, MSH6, and @GENE$). 11 @GENE$ codon 12/13 mutations were screened with Sanger sequencing. 12 Functional MMR assay In vitro MMR activity assay was performed as previously described. 13 RESULTS We performed germline whole-exome sequencing on three CRC patients diagnosed before 60 years of age (III-1, III-7, III-8, Figure 1A) and who belonged to a CRC family comprising of seven cancer patients divided over two generations. Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: c.3299C > T, @VARIANT$) and MUTYH (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,PMS2;133560,KRAS;37990,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0 +"Four genes (including AGXT2, @GENE$, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,ZFHX3;21366,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +"In this family, the patient (II: 1) with digenic heterozygous mutations of KCNH2 p.307_308del and @GENE$ @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without @GENE$ @VARIANT$ showed normal QT intervals and cardiac function.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,VPS13C;41188,MRPL15;32210,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0 +"25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25 The contribution of the genetic variants, other than @GENE$ and @GENE$, to cancer risk cannot be completely excluded.",7689793,MSH6;149,MUTYH;8156,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0 +"One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$).",5887939,CELSR2;1078,FAT4;14377,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0 +"The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and HNF4A @VARIANT$. Both mutations are novel and whilst a different mutation, R80W, has been reported in @GENE$, further evidence to support the pathogenicity of E508K is lacking.",4090307,HNF1A;459,HNF4A;395,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R80Q;tmVar:p|SUB|R|80|Q;HGVS:p.R80Q;VariantGroup:2;CorrespondingGene:3172,0 +"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0 +"Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0 +"Proband 17 inherited @GENE$ p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out. Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants.",8152424,CHD7;19067,FGFR1;69065,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0 +"The creation of the downstream acceptor splice site results in 3 bp deletion (@VARIANT$). A heterozygous 3 bp deletion is clearly visible in the sequencing data derived from P3, but not in C1. G, The 3 bp deletion causes the deletion of p.Gly74. The deleted nucleotides are enclosed in the red box. H, A multiple alignment analysis shows that p.Gly74 is conserved among Eukaryotic species ACADS and ECHDC1 deficiencies act in synergy on cellular EMA excretion Having shown that 3/82 SCADD individuals with common ACADS variants were heterozygous for loss-of-function ECHDC1 variants, we speculated that ECHDC1 haploinsufficiency, in combination with the common @GENE$ @VARIANT$ variant, had an additive effect on EMA levels. To further examine this hypothesis, we measured EMA levels in cultured fibroblasts from healthy individuals, who were either wild-type, heterozygous or homozygous for ACADS c.625G>A, with or without approximately halved knockdown of ECHDC1 mRNA levels (Figure 5). The six cell lines were constructed by transduction either with non-targeting shRNA or with @GENE$ targeting shRNA.",8518634,ACADS;20057,ECHDC1;23106,c.221_223del;tmVar:c|DEL|221_223|;HGVS:c.221_223del;VariantGroup:10;CorrespondingGene:55862,c.625G>A;tmVar:c|SUB|G|625|A;HGVS:c.625G>A;VariantGroup:1;CorrespondingGene:35;RS#:1799958;CA#:145599,0 +"myc-pendrin A372V, L445W, @VARIANT$, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected. f Relative amount of cell surface pendrin is shown. Mean +- SEM; one-way ANOVA; **p < 0.01; *p < 0.05; (n = 3). Source data are provided as a Source Data file. Several amino-acid substitutions of @GENE$ have been identified from Pendred syndrome patients as well as non-syndromic hearing loss patients with EVA.",7067772,EphA2;20929,pendrin;20132,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0 +"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,UNC13B;31376,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of @GENE$ @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (KRAS @VARIANT$) was absent in this tumor, which points toward retained @GENE$ repair activity.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137,0 +"There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0 +"KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, @GENE$-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"The loss-of-function variation in @GENE$ or @GENE$ (e.g., CACNA1C-Q1916R), which produces inadequate inward hybrid currents, is responsible for the pathopoiesis of ERS. Thus, from the mechanistic point of view, INa and ICa-L show a synergistic effect on the repolarization as two ingredients of the inward currents. In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental CACNA1C-@VARIANT$ mutation might be partly compensated by the persistent inward tail INa produced by the SCN5A-@VARIANT$ channel.",5426766,SCN5A;22738,CACNA1C;55484,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1 +"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,LAMA2;37306,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0 +"Nonetheless, recent studies proved that @GENE$ variants have a role in ALS. According to earlier studies, KIF5A variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious.",6707335,KIF5A;55861,SPG11;41614,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and TAF15 @VARIANT$ with @GENE$ p.I2547T and SETX p.T14I).,4293318,VAPB;36163,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,KCNH2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"M2, CYP1B1: @VARIANT$. M3, @GENE$: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0 +"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0 +"Two variants, likely pathogenic @VARIANT$ and pathogenic @VARIANT$, in HMBS were found in two subjects. Pathogenic variants in HMBS are associated with Acute Intermittent Porphyria. We consider HMBS variants as incidental findings that are likely unrelated to phenotype. Variant segregation in subjects All subjects were heterozygous carriers of pathogenic or deleterious variants in genes known to affect various enzymatic pathways of cellular energy. Five subjects (R279, R410, R465, R469 and R470) carried pathogenic and deleterious variants in genes known to affect glycogen metabolism (GBE1, PYGM), FAO (ACADVL and CPT2), fatty acid and amino acid catabolism (PCCB), oxidative phosphorylation (ELAC2, NDUFA6, NDUFA10 and @GENE$), mitochondrial matrix enzymes (OAT and TIMM50). Two subjects (R302 and R462) had variants in genes involved in Ca 2+ regulation (RYR1 and CACNA1S), glycogen metabolism (GBE1 and @GENE$) and oxidative phosphorylation (NDUFS8).",6072915,NUBPL;11854,PHKA1;1981,p. R175W;tmVar:p|SUB|R|175|W;HGVS:p.R175W;VariantGroup:4;CorrespondingGene:5256;RS#:376233279;CA#:10361894,p. R225Q;tmVar:p|SUB|R|225|Q;HGVS:p.R225Q;VariantGroup:11;CorrespondingGene:779,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and @GENE$-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +" CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2). DISCUSSION In this study, we performed exome sequencing on 584 patients with @GENE$ and without a molecular diagnosis. Variants in seven @GENE$-mediated genes involved in somitogenesis were selected for analysis.",7549550,CS;56073,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,1 +"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1 +"To further analyze the role of @GENE$ in Pendred syndrome, direct sequencing of the EPHA2 gene in 40 Japanese hearing loss patients with EVA carrying mono-allelic mutation of SLC26A4 were examined. While mutation of ~70 genes causing hearing loss were previously identified as a human nonsyndromic deafness gene, they were not identified in these patients. On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b). These EPHA2 mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of @GENE$ was previously reported.",7067772,EphA2;20929,SLC26A4;20132,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,0 +"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +">G (p.Asn692Ser) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (@VARIANT$) was identified in @GENE$ (table 1).",6161649,CDH2;20424,IL17RD;9717,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"For example, two variants in proband P15, @VARIANT$ in PROKR2 and p. Tyr503His in @GENE$ (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DMXL2;41022,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0 +"In the individual carrying the @VARIANT$ @GENE$ variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain.",6707335,NEFH;40755,GRN;1577,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,1 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo. In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions.",6161649,MAP4K4;7442,CDH2;20424,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0 +"The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes. ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of @GENE$ were detected.",3842385,EDA;1896,WNT10A;22525,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"@GENE$ gene might interact with @GENE$ gene product and give rise to the spectrum of phenotype varying from severe phenotype with complete penetrance to partial features. Conclusion In this study, we analysed a large family segregating Waardenburg syndrome type 2 to identify the underlying genetic defects. Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the MITF gene and a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the C2orf74 was identified.",7877624,C2orf74;49849,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,1 +"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2).",3125325,USH1G;56113,MYO7A;219,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0 +"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and c.353A > G (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"For a more comprehensive review of the role of GATA4 in CHD we refer to Ref.. By contrast, the few @GENE$ missense mutations found in 46,XY DSD individuals with or without CHD are all located in the N-terminal zinc finger domain, which is responsible for DNA binding and interaction with cofactors. Functional characterization of GATA4 variants with respect to the 46,XY DSD phenotype has only been performed for the p.Gly221Arg mutation so far. In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor FOG2. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the @GENE$ promoter for GATA4 variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only @VARIANT$ and @VARIANT$ are close to Zn binding sites.",5893726,GATA4;1551,CYP17;73875,Gly221;tmVar:p|Allele|G|221;VariantGroup:4;RS#:398122402(Expired),Cys238;tmVar:p|Allele|C|238;VariantGroup:0;CorrespondingGene:2626,0 +"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"One missense mutation (@VARIANT$) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female @GENE$-Q1916R mutation carriers, which led to the incomplete penetrance.",5426766,SCN5A;22738,CACNA1C;55484,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,1 +"Six variants in @GENE$ occurred de-novo, three of which were not previously described: @VARIANT$.(Asp1079Alafs*25), c.8860G>T p.(Glu2954*), and c.9201+1G>A. One de-novo and novel variant was also detected in @GENE$: c.992G>A p.(@VARIANT$).",7224062,PKD1;250,PKD2;20104,c.3236del p;tmVar:c|DEL|3236|P;HGVS:c.3236delP;VariantGroup:47;CorrespondingGene:5310,Cys331Tyr;tmVar:p|SUB|C|331|Y;HGVS:p.C331Y;VariantGroup:1;CorrespondingGene:23193;RS#:144118755,0 +"The p.(@VARIANT$) mutation was predicted to be highly destabilizing. (C) Alignment of P4B3 domain (a.a. 1059-1097 of human @GENE$). While @VARIANT$ is highly conserved among orthologs of LRP6 and @GENE$, zebrafish LRP5 and Drosophila Arrow use threonine and aspartate, respectively, at this position.",8621929,LRP6;1747,LRP5;1746,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asparagine1075;tmVar:p|Allele|N|1075;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR1;7665,PTK7;43672,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0 +"Digenic Inheritance of @GENE$ and @GENE$ Mutations in Patient with Infantile Dilated Cardiomyopathy Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in MYH7 (@VARIANT$; @VARIANT$).",6359299,LAMA4;37604,MYH7;68044,c.2770G > A;tmVar:c|SUB|G|2770|A;HGVS:c.2770G>A;VariantGroup:0;CorrespondingGene:3910;RS#:121913628;CA#:13034,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,0 +"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; @VARIANT$) and USH2A (c.9921T>G).",3125325,CDH23;11142,USH1G;56113,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0 +"Mice lacking @GENE$ develop cardiomyopathy and have an increased frequency of sudden death upon stress; electron microscopy of these mice revealed malformed blood vessels and micro-circulation abnormalities. Moreover, patients carrying a LAMA4 Pro943Leu mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYH7;68044,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0 +"This is in line with the data from previous studies; according to which, @GENE$ is a causative gene of ALS-FTD. The NEK1 @VARIANT$ variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein. A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form.",6707335,TBK1;22742,CCNF;1335,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0 +"Our results indicate that the novel @GENE$-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The ORVAL prediction revealed five disease-causing digenic combinations involving DUSP6, ANOS1, @GENE$, PLXNA1, PROP1, and @GENE$ genes (Table 3). The absence of variant combinations involving the PROKR2 gene variant @VARIANT$ excludes its implication in digenic inheritance in the index case (HH12). Furthermore, since the variant is novel and has no functional evidence of pathogenicity, it is likely to be benign. Further molecular studies are needed to prove the deleterious character of the PROKR2 Lys205del variant. Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(Val114Leu)].",8446458,DCC;21081,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0 +"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel @VARIANT$ variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0 +"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The DUSP6 gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0 +"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0 +"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), @GENE$: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,1 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0 +"Only three variants were homozygous in three patients: (1) @GENE$: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0 +"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (@VARIANT$), @GENE$ (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,CAPN3;52,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0 +"The mother and son reported by Beijers et al. were heterozygous for @GENE$ G31D and HNF4A @VARIANT$, but the @VARIANT$ substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/). It is therefore unlikely to be causative of MODY. The proband described by Forlani et al. was heterozygous for HNF1A E508K and @GENE$ R80Q.",4090307,HNF1A;459,HNF4A;395,H214Y;tmVar:p|SUB|H|214|Y;HGVS:p.H214Y;VariantGroup:5;CorrespondingGene:3172,G31D;tmVar:p|SUB|G|31|D;HGVS:p.G31D;VariantGroup:4;CorrespondingGene:6927;RS#:137853247;CA#:124487,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The genotypes of @GENE$ (NM_001257180.2: @VARIANT$, p.His596Arg) and @GENE$ (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"A single-nucleotide duplication (@VARIANT$/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (@VARIANT$/p.Cys520Tyr) that cosegregated with both the AI phenotype and the @GENE$ mutation.",6785452,LAMA3;18279,ENAM;9698,c.395dupA;tmVar:c|DUP|395|A|;HGVS:c.395dupA;VariantGroup:18;CorrespondingGene:13801,c.1559G>A;tmVar:c|SUB|G|1559|A;HGVS:c.1559G>A;VariantGroup:6;CorrespondingGene:3909,0 +"Among the 8 novel variants, 4 were classified as P (p.C176R and @VARIANT$ in @GENE$, @VARIANT$ in @GENE$) or LP (p.D137E in DUOX2), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253,p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506,0 +"We identified four genetic variants (KCNQ1-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and @GENE$-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and @GENE$-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNE1;3753,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0 +"One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare @GENE$ missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FZD6;2617,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0 +"Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (@VARIANT$) and TNNT2 (@VARIANT$), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; @GENE$:part of the sarcomere, and @GENE$:part of the ECM/signalling component.",6359299,MYH7;68044,LAMA4;37604,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0 +"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"On the other hand, EphA2 overexpression did not affect localization of @VARIANT$. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) @GENE$ (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f).",7067772,pendrin;20132,ephrin-B2;3019,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0 +" A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, was identified in patient #3. BBS1, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of @GENE$ and @GENE$ lie in this portion.",6567512,BBS2;12122,BBS7;12395,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, @VARIANT$) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Met1445Val;tmVar:p|SUB|M|1445|V;HGVS:p.M1445V;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; @VARIANT$) c.1226A>G; @VARIANT$ and @GENE$ (MIM 600509; NM_000352.4; rs151344623) c.3989-9G>A mutations.,5505202,GBA;68040,ABCC8;68048,rs7673715;tmVar:rs7673715;VariantGroup:2;RS#:7673715,p.N409S;tmVar:p|SUB|N|409|S;HGVS:p.N409S;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0 +"Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, FGF10, @GENE$, RIPK4 and EYA1; and RET for PIK3R3 with @GENE$, which also is connected with RIPK4.",6726737,GLI2;12725,PTPN11;2122,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0 +"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 + LIMITATIONS Our study was performed only in the statistical field on @GENE$ @VARIANT$ and @GENE$ @VARIANT$ by WES and predisposing genes analyses.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ @VARIANT$, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0 +" In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes @GENE$, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant c.676G>A (@VARIANT$) was identified in IL17RD (table 1). IL17RD is highly expressed in vessel endothelial cells and vascularised organs, where it inhibits fibroblast growth factor (FGF) and plays critical roles in endothelial cell proliferation and angiogenesis. In contrast to FGF inhibition, overexpression of @GENE$ attenuates the degradation of epidermal growth factor recepter (EGFR) and enhances downstream MAPK signalling (figure 3).",6161649,N-cadherin;20424,IL17RD;9717,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588,0 +"(A) The alignment of orthologs of the human @GENE$ protein. The R171 and G213 residues are represented by arrowheads. (B) The predicted 2D structure of human WNT10A protein. The @VARIANT$ and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. @VARIANT$ is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The G257 and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the EDA trimer. (B) The side view of the @GENE$ trimer.",3842385,WNT10A;22525,EDA;1896,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,I312;tmVar:p|Allele|I|312;VariantGroup:7;CorrespondingGene:1896,0 +"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with BSP+ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates @GENE$ missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,TOR2A;25260,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0 +"Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and @GENE$ p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Two potential disease-causing mutations were identified: (d) ENAM: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) LAMA3 missense mutation @VARIANT$/p.Cys520Tyr. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (@GENE$ and @GENE$) mutations.",6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,c.1559G>A;tmVar:c|SUB|G|1559|A;HGVS:c.1559G>A;VariantGroup:6;CorrespondingGene:3909,1 +"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (c.46C>G; p.L16V) and @GENE$ (@VARIANT$).",3125325,USH1G;56113,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0 +"The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/@GENE$ @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"In this family, the evidence-based on the genetic and functional findings indicated that the loss-of-function mutation @GENE$-@VARIANT$ was the detrimental variation, and that the gain-of-function variant SCN5A-R1193Q modulated the phenotype. The candidate genes of ERS included CACNA1C and SCN5A, which suggests that the interaction of variations in these 2 genes may potentially modify the penetrance of ERS phenotypes. As previously reported, @GENE$-@VARIANT$ channels showed inactivation gating and generated a persistent, non-inactivating inward sodium current (INa), which was associated with LQTS.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0 +"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and @VARIANT$ variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form.",6707335,GRN;1577,SIGMAR1;39965,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0 +"To the best of our knowledge, two of the identified variants (FOXC2: @VARIANT$, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,0 +"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"On the other hand, mis-localization of pendrin @VARIANT$ from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding. Here, we found that @GENE$ A372V, L445W, Q446R, and G672E did not bind to EphA2. Given the fact that loss of EphA2 disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with @GENE$. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation.",7067772,pendrin;20132,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the @GENE$ repeat expansion or a missense variant in SOD1 in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$).",4293318,C9ORF72;10137,FUS;2521,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0 +"Although the majority of @GENE$ mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging. In the @GENE$ gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and @VARIANT$).",6707335,FUS;2521,TBK1;22742,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,0 +"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and @GENE$, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary @GENE$-binding site.",5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"25 The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and @GENE$ (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21 TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24 Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in @GENE$ might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients.",7689793,EBNA1BP2;4969,CAPN9;38208,c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,TACR3;824,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I).,4293318,VAPB;36163,TAF15;131088,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0 +"The mother and son reported by Beijers et al. were heterozygous for HNF1A G31D and @GENE$ @VARIANT$, but the G31D substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/). It is therefore unlikely to be causative of MODY. The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and HNF4A R80Q.",4090307,HNF4A;395,HNF1A;459,H214Y;tmVar:p|SUB|H|214|Y;HGVS:p.H214Y;VariantGroup:5;CorrespondingGene:3172,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,0 +" CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. @GENE$ @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Limb Girdle Muscular Dystrophy due to Digenic Inheritance of @GENE$ and @GENE$ Mutations We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (@VARIANT$), CAPN3 (@VARIANT$), and DES (rs144901249) genes.",6180278,DES;56469,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0 +"Statistical analysis of pro-COL1A1 colocalization with endoplasmic reticulum (ER) or trans-Golgi by confocal microscopy Genotype of cell line Manders coefficient (M2) ER (PDI) overlapping pro-@GENE$ trans-Golgi (TGN38) overlapping pro-COL1A1 Wt 0.86 (N = 19) 0.11 (N = 27) SEC23Ac.1200G>C/+ 0.79 (N = 16) 0.13 (N = 28) SEC23Ac.1200G>C/+ MAN1B1@VARIANT$/+ 0.69*** (N = 59) 0.17* (N = 150) SEC23Ac.1200G>C/c.@VARIANT$; @GENE$c.1000C>T/c.1000C>T 0.73*** (N = 41) 0.18** (N = 138) To determine whether increased intracellular levels of pro-COL1A1 were due to abnormal accumulation of this protein in the Golgi of mutant cells, double immunofluorescence confocal microscopy with antibodies against pro-COL1A1 and TGN38, an integral membrane protein in the trans-Golgi, was performed.",4853519,COL1A1;73874,MAN1B1;5230,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,0 +"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,TBK1;22742,OPTN;11085,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0 +"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +"Moreover, the presence of other variants (KCNQ1-p.R583H, @GENE$-@VARIANT$, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1 +"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,UNC13B;31376,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +"Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"We identified four genetic variants (@GENE$-p.R583H, KCNH2-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0 +"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Furthermore, @GENE$ presented 2 variants in patient 1. Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. @GENE$ for EVC, FGF10, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with RIPK4.",6726737,RIPK4;10772,GLI3;139,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0 +"A nonsense variant in @GENE$ (NM_000625.4: c.2059C>T, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. ATP2A3 is highly expressed in cerebellar Purkinje cells (Allen Brain Atlas) and is a member of the P-type ATPase superfamily that includes the gene (@GENE$) causally associated with rapid-onset dystonia-Parkinsonism (DYT12). GNA14 and HS1BP3 variants in pedigree with BSP+ and Parkinsonism A novel HS1BP3 nonsynonymous SNV (c.94C>A [NM_022460.3], @VARIANT$ [NP_071905.3]) was found in a father and son with severe BSP+ (Family 10043; Figure 6; Tables 1, 5, 8 and S2; Data S1).",6081235,NOS2;55473,ATP1A3;113729,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"@GENE$ @VARIANT$ and SCN5A @VARIANT$ of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ p.R1865H.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense @GENE$ variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,SOS1;4117,c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0 +"We propose that cysteine to arginine change in position 238 of GATA4 lacks activity to bind DNA reducing the transactivation of @GENE$ critically. By contrast, variants @VARIANT$ and p@VARIANT$ found in cases 2 and 3 did not affect @GENE$ promoter activity.",5893726,AMH;68060,CYP17;73875,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0 +"Variant in @GENE$ (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well. No potentially pathogenic rare variant was identified. In order to identify variant(s) in other genes which might influence the expressivity of WS phenotype in our cases, exome data was filtered by using an unbiased and hypothesis-free approach. A rare missense variant (c.101T>G; @VARIANT$) in the C2orf74 gene was identified in both affected individuals.",7877624,TYRO3;4585,RNF43;37742,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (@VARIANT$; p.E2135fsX31), and six missense mutations, four of which (@VARIANT$, p.R1379P, p.D2639G, and p.R3043W) had not been previously reported. They affect amino acid residues located in the 11th, 13th and 25th cadherin repeat and the extracellular region adjacent to the transmembrane domain (3065-3085), respectively (Tables 2, 3 Figure 1). Intriguingly, the p.R1060W mutation, which affects a residue in the 10th cadherin repeat that belongs to a canonical motif (DRE) predicted to bind Ca2+ , has previously been reported in an isolated form of deafness, DFNB12 (cited in Astuto et al.). Two pathogenic or presumably pathogenic mutations in @GENE$, specifically, a nonsense mutation (p.R991X) and a novel missense mutation (p.R1273S), were found in two patients.",3125325,CDH23;11142,PCDH15;23401,c.6404_6405delAG;tmVar:c|DEL|6404_6405|AG;HGVS:c.6404_6405delAG;VariantGroup:207;CorrespondingGene:65217,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in @GENE$, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in USH2A.",3125325,MYO7A;219,USH1C;77476,c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0 +"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +The @GENE$ variant @VARIANT$ did not show significant protein stability differences with the wild-type protein (Fig 6C and Fig 6D). @GENE$ @VARIANT$ variant decreases protein stability.,6338360,PITX2;55454,FOXC2;21091,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.H395N;tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0 +"Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,COL6A3;37917,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,CHD7;19067,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,0 +"Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue TCF3 @VARIANT$ mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of TACI gene in the proband II.2.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +" CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in @GENE$ and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MYOD1;7857,TBX6;3389,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0 +A male (ID104) was found to have a heterozygous missense variant @VARIANT$ (p.Lys330Met) in EHMT1 and a missense variant c.1777C > G (@VARIANT$) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases.,7463850,SLC9A6;55971,EHMT1;11698,c.989A > T;tmVar:c|SUB|A|989|T;HGVS:c.989A>T;VariantGroup:1;CorrespondingGene:79813;RS#:764291502;CA#:5375151,p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,0 +"We found that @GENE$ variant @VARIANT$ lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and Pro226Leu activated the @GENE$ promoter similar to wt.",5893726,GATA4;1551,CYP17;73875,Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,SCRIB;44228,FZD1;20750,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"For Case 1, a novel missense VUS (variant of unknown significance) variant (c.361C>T; @VARIANT$) in the @GENE$ gene was identified in the patient and his father. A rare variant in @GENE$, @VARIANT$; p.Thr143Ile, was detected in Case 2 and was classified as VUS.",7696449,STAR;297,AMH;68060,p.Arg121Trp;tmVar:p|SUB|R|121|W;HGVS:p.R121W;VariantGroup:7;CorrespondingGene:6770;RS#:34908868;CA#:4715265,c.428C>T;tmVar:c|SUB|C|428|T;HGVS:c.428C>T;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,0 +"Of the 3 novel variants in @GENE$, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and @VARIANT$ and p.E389K were missense mutations located in the peroxidase-like domain (Fig. S3A). A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, DUOXA2 and @GENE$). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,DUOX2;9689,TPO;461,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,0 +"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0 +"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel @GENE$ missense variant c.10147G>A).",5887939,CELSR1;7665,FAT4;14377,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0 +"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (g.68531T>G, c.503T>G, p.Met168Arg; @VARIANT$, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (WNT10A c.637G>A, rs147680216) in EAS.",8621929,WNT10A;22525,LRP6;1747,g.112084C>G;tmVar:g|SUB|C|112084|G;HGVS:g.112084C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"We found that @GENE$-@VARIANT$ was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and @GENE$-@VARIANT$ were previously reported to produce more severe phenotypes when combined with disease-causing alleles.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Notably, the common variants @GENE$-@VARIANT$ and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Although the majority of @GENE$ mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging. In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (@VARIANT$) were identified in our patient cohort. The patient (#90u) carrying the novel K631del deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90. @GENE$ variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and @VARIANT$).",6707335,FUS;2521,CCNF;1335,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,0 +"In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and @VARIANT$(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of KAl1 gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function. Prokineticin-2 (@GENE$) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed PROK2/@GENE$ variants, which was significantly higher than the 9% in the Caucasian population.",8796337,PROK2;9268,PROKR2;16368,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,c.1524del A;tmVar:c|DEL|1524|A;HGVS:c.1524delA;VariantGroup:17;CorrespondingGene:3730,0 +"Moreover, gain-of-function mutation of SCN5A commonly induced LQTS, while loss-of-function mutation of @GENE$ ordinary led to sinoatrial node dysfunction, atrioventricular block, atrial fibrillation and cardiomyopathy (e.g., ARVC/D; Blana et al.,; Han et al.,). Therefore, in this study, SCN5A @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0 +"Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in @GENE$ (c.1175C>T, @VARIANT$) and a heterozygous variant in @GENE$ (c.1070A>G, @VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1 +"Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and @VARIANT$ in @GENE$ as well as F193C, S198F and @VARIANT$ in @GENE$, have been reported previously in patients with hearing impairment.",2737700,Cx26;2975,Cx32;137,A197S;tmVar:p|SUB|A|197|S;HGVS:p.A197S;VariantGroup:3;CorrespondingGene:2706;RS#:777236559,G199R;tmVar:p|SUB|G|199|R;HGVS:p.G199R;VariantGroup:17;CorrespondingGene:2705,0 +"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK @VARIANT$ and HA-@GENE$ Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0 +"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively. Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, @GENE$, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, @GENE$, and BCL9L) as well.",7877624,LRP4;17964,BCL9;3191,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0 +"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,KCNH2;201,LQT6;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,1 +"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for @GENE$ , 11%-15% for @GENE$ , and for USH2A in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor.",3125325,CDH23;11142,PCDH15;23401,c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0 +"Exome sequencing performed with DNA from Patient 3 identified 13 homozygous variants that were rare and predicted to be deleterious (Table S1 in the Supplementary Appendix), 2 of which were also homozygous in the two other affected siblings: @GENE$ (NM_207111.3) c.2251C T, @VARIANT$ and @GENE$ (NM_001102653.1) c.998G T, @VARIANT$; these variants were not identified or were heterozygous in the unaffected family members (Fig. 1).",3738065,RNF216;19442,OTUD4;35370,p.R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,p.G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,1 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0 +(B) The predicted 2D structure of human @GENE$ protein. The R171 and @VARIANT$ residues are in yellow. The 3D structure of @GENE$ is shown in Figure 4. The @VARIANT$ residue is located at the interface of two trimers.,3842385,WNT10A;22525,EDA;1896,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,G257;tmVar:c|Allele|G|257;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), MBD5 (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0 +"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$ Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, @GENE$-@VARIANT$, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1 +"Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Among the 18 variants, three missense variations, the new @GENE$ mutation (@VARIANT$) and the known IL10RA missense variants (@VARIANT$ and G351R), caught our attention: we hypothesized that these three variants might together contribute to an increased risk of developing early onset IBD. Variants in combined heterozygosis on different genes may have a cumulative effect and contribute to the disease phenotype, probably due to the dysregulation of different pathways. Digenic contribution to multigenic diseases is poorly investigated by GWAS studies. However, recent data showed that digenic or multigenic inheritance might be underrated mechanisms explaining familial recurrence of multifactorial diseases. IL10RA (11q23) and @GENE$ (21q22) are attractive inflammatory bowel disease candidate genes: they encode for the alpha and beta chain, respectively, that form a tetrameric cell bound structure able to bind interleukin (IL-10).",3975370,NOD2;11156,IL10RB;523,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0 +"Mutations in @GENE$ and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +"(c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type @GENE$ (Table 3), KCNH2 @VARIANT$ showed a decreasing trend in molecular weight and increasing instability. However, the prediction of theoretical pI, aliphatic index and GRAVY presented no significant differences. Compared to the Nav1.5 protein properties of wild-type @GENE$, SCN5A p.R1865H slightly increased its molecular weight and aliphatic index but reduced its instability index.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"These two individuals were heterozygous carriers of p.R1141X mutation in ABCC6 and @VARIANT$ in @GENE$. Since heterozygous carriers of @VARIANT$ in @GENE$ alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +"R583H mutant channels were investigated by analyzing ionic currents from cells expressing the wild-type (WT) channel (@GENE$-WT) or KCNQ1-p.R583H and from cells co-expressing the KCNQ1 and KCNE1 subunits (KCNQ1-WT+KCNE1 or KCNQ1-@VARIANT$+KCNE1), which reconstitute the slow delayed rectifier potassium current (IKs). The functional consequence of KCNH2-p.C108Y was investigated by analyzing the ionic currents from cells expressing @GENE$-WT or KCNH2-@VARIANT$ and from cells co-expressing both alleles.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0 +"Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of @GENE$ were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,SEMA7A;2678,PROKR2;16368,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709,0 +"Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"This analysis indicated that the CAPN3 variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the DES gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,1 +"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"(A) Segregation of the @GENE$-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Genotypes: @GENE$ p.Thr1100Met (@VARIANT$; blue); @GENE$ @VARIANT$ (Y179C; green); -, wild type.",7689793,MSH6;149,MUTYH;8156,T1100M;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0 +"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0 +"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous p.A194T mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,KCNH2;201,KCNE2;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,1 +"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Three variants in three genes were rare, including the @GENE$ gene mutation [@VARIANT$], a novel heterozygous missense variant [@VARIANT$; p.(Glu436Lys)] in the @GENE$ gene (NM_001146029), as well as a splice site variation in the PLXNA1 gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,PROKR2;16368,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"(a) Digenic inheritance of @GENE$ (@VARIANT$, C104R TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ @VARIANT$ mutation (as indicated).",5671988,TNFRSF13B;49320,TCF3;2408,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS.",7689793,TRIP6;37757,CAPN9;38208,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0 +"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX @VARIANT$ and SETX p.T14I).",4293318,SOD1;392,FUS;2521,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0 +"A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven. Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous @GENE$ and @GENE$ variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy.",5868303,TIA1;20692,SQSTM1;31202,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +" In patient AVM427, the de novo heterozygous missense variant @VARIANT$ (p.Asp1148Tyr) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to Smad1-mediated @GENE$ signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-@GENE$ complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, @VARIANT$ (p.Glu631Ter), in EGFR (table 1).",6161649,BMP;55955,Smad4;31310,c.3442G>T;tmVar:c|SUB|G|3442|T;HGVS:c.3442G>T;VariantGroup:3;CorrespondingGene:9765,c.1891G>T;tmVar:c|SUB|G|1891|T;HGVS:c.1891G>T;VariantGroup:8;RS#:909905659,0 +"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,CELSR1;7665,DVL3;20928,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0 +"Four genes (including AGXT2, @GENE$, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,ZFHX3;21366,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +"Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The mutations of @GENE$ @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous @GENE$ @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0 +A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in @GENE$ and a missense variant @VARIANT$ (p.Leu593Val) in @GENE$. Limited clinical information was available about this male.,7463850,EHMT1;11698,SLC9A6;55971,p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,1 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in USH2A.",3125325,MYO7A;219,USH1C;77476,c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0 +" CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MYOD1;7857,TBX6;3389,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0 +"Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and KCNQ1-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. Primers used for mutagenesis are available upon request. The KCNH2-WT, @GENE$-WT, and mutant coding sequences were engineered in bicistronic mammalian vectors pIRES2-EGFP (Biosciences-Clontech, Palo Alto, CA, USA).",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"A total of 2 novel variants, p.S309P and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. @VARIANT$ is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and p.K618* are located in the cytoplasmic loops (Fig. S3C). Patients with GIS had a higher tendency to be affected with mutations than patients with TD [25/32 (78%) vs. 6/11 (54%), Fig. 2]. Variants in TG, @GENE$, DUOXA2, SLC5A5 and PROP1 genes were found exclusively in patients with GIS, and 1 variant in TRHR was found in patients with TD. Other genes, including DUOX2, TPO and @GENE$, were associated with either dysgenesis or GIS phenotype (Table II and Fig. 1B).",7248516,TSHR;315,SLC26A4;20132,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,0 +"Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes. ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of WNT10A were detected.",3842385,WNT10A;22525,EDA;1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0 +"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0 +"These include complete conservation of @VARIANT$ (Figures S1-S4), SIFT analysis, and protein modeling. Furthermore, protein expression was markedly reduced in vitro, providing additional support for a deleterious effect. This patient with the p.Ala253Thr @GENE$ missense mutation also had a hemizygous @GENE$ deletion of the completely conserved @VARIANT$ within the whey-acidic-protein (WAP) domain that forms a disulphide bridge with Cys134 of anosmin-1 (Figure S1C,D).",3888818,NELF;10648,KAL1;55445,Ala253;tmVar:p|Allele|A|253;VariantGroup:3;CorrespondingGene:26012;RS#:142726563,Cys163;tmVar:p|Allele|C|163;VariantGroup:9;CorrespondingGene:3730,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, @VARIANT$ in @GENE$, and c.2299delG and @VARIANT$ in USH2A.",3125325,MYO7A;219,USH1C;77476,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0 +"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within @GENE$, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3).",6161649,SMAD1;21196,BMP;55955,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0 +"Because charged residues are important for proteins trafficking, the A194T may result in accumulation of the @GENE$ protein in intracellular compartments such as the Golgi apparatus or in other sites such as the endoplasmic reticulum or lysosomes. The A194T substitution might cause conformational changes within the Cx31 molecule or affect the ability of Cx31 to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in Cx26 as well as @VARIANT$, S198F and G199R in @GENE$, have been reported previously in patients with hearing impairment.",2737700,Cx31;7338,Cx32;137,N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851,F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, @GENE$-@VARIANT$, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in @GENE$, ANOS1, @GENE$, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,DUSP6;55621,DCC;21081,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +" In a second example, we identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014). Additionally, the @VARIANT$ @GENE$ change has been previously found to be causative of micropenis, where it was found in compound heterozygosity or homozygosity in three individuals (Sasaki et al., 2003).",5765430,SF1;138518,SRD5A2;37292,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681,0 +"In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in @GENE$ (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in @GENE$ (@VARIANT$; @VARIANT$).",6359299,LAMA4;37604,MYH7;68044,c.2770G > A;tmVar:c|SUB|G|2770|A;HGVS:c.2770G>A;VariantGroup:0;CorrespondingGene:3910;RS#:121913628;CA#:13034,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,0 +None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:@VARIANT$; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).,6053831,PCDH15;23401,USH1G;56113,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,72915838C > T;tmVar:g|SUB|C|72915838|T;HGVS:g.72915838C>T;VariantGroup:1;CorrespondingGene:124590;RS#:538983393;CA#:8753931,1 +"Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EPHA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0 +"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0 +"Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and KCNQ1-c.G1748A (@VARIANT$) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"Mutations in the @GENE$ and @GENE$ Genes in a Family with Pseudoxanthoma Elasticum-like Phenotypes A characteristic feature of classic PXE, an autosomal recessive disorder caused by mutations in the ABCC6 gene, is aberrant mineralization of connective tissues, particularly the elastic fibers. Here, we report a family with PXE-like cutaneous features in association with multiple coagulation factor deficiency, an autosomal recessive disorder associated with GGCX mutations. The proband and her sister, both with severe skin findings with extensive mineralization, were compound heterozygotes for missense mutations in the GGCX gene, which were shown to result in reduced gamma-glutamyl carboxylase activity and in under-carboxylation of matrix gla protein. The proband's mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (@VARIANT$) in GGCX and a null mutation (@VARIANT$) in the ABCC6 gene, suggesting digenic nature of their skin findings.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,1 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,FUS;2521,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0 +"20 The identified CUX1 (NM_001202543: @VARIANT$, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include @GENE$, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,RYR3;68151,CAPN9;38208,c.1438A > G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,0 +"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS.",8621929,LRP6;1747,WNT10A;22525,rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,FZD1;20750,FAT4;14377,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0 +"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different @GENE$ mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1 +"For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug @GENE$-WT or 1 mug KCNQ1-@VARIANT$ + 1 mug KCNE1-WT) or 3 mug (1.5 mug KCNH2-WT + 1.5 mug KCNH2-@VARIANT$ or 1.5 mug @GENE$-WT + 1.5 mug empty vector) plasmid per dish were used.",5578023,KCNE1;3753,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0 +"Pedigree and sequence chromatograms of the patient with the @VARIANT$ in @GENE$ and c.158-1G>A in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in MYO7A. Another variation, @VARIANT$ in intron 3 of PCDH15, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0 +"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal @GENE$ domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary CYP1B1-binding site.",5953556,CYP1B1;68035,TEK;397,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010,0 +"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and @GENE$ p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,LAMA2;37306,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757,0 +"On the other hand, mis-localization of @GENE$ A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding. Here, we found that pendrin A372V, L445W, Q446R, and @VARIANT$ did not bind to EphA2. Given the fact that loss of @GENE$ disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation.",7067772,pendrin;20132,EphA2;20929,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +" In patient AVM359, the de novo heterozygous missense variant c.1592G>A (p.Cys531Tyr) was identified in @GENE$ (table 1), which encodes a membrane-associated multidomain protein. The variant is predicted to affect a conserved site (SIFT=0, PolyPhen2=1, GERP++=5.68, CADD=24.6). SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within @GENE$, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).",6161649,SCUBE2;36383,SMAD1;21196,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0 +"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0 +"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0 +"The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of PROKR2 were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,DUSP6;55621,SEMA7A;2678,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709,0 +"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0 +" Recently, Gifford et al., identified three missense variants in @GENE$ (Gln670His), @GENE$ (@VARIANT$), and NKX2-5 (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MKL2;40917,MYH7;68044,Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625,Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058,0 +"However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of @GENE$ protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction. LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and SCN5A @VARIANT$ by WES and predisposing genes analyses.",8739608,KCNH2;201,Nav1.5;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"@GENE$-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0 +"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and @VARIANT$; @GENE$: @VARIANT$). In summary, the increased frequency in PCG patients of rare @GENE$ and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,PITX2;55454,FOXC2;21091,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0 +"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; @VARIANT$] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a). The @GENE$ variant [NM_033056: c.3101G > A; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,USH1G;56113,PCDH15;23401,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,p.(Arg1034His);tmVar:p|SUB|R|1034|H;HGVS:p.R1034H;VariantGroup:2;CorrespondingGene:124590,0 +"(A) In addition to c.235delC in GJB2, the de novo variant of @GENE$, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor. By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous p.A194T mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,MITF;4892,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,SNAI3;8500,TYRO3;4585,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 @VARIANT$, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0 +"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"M1, CYP1B1: @VARIANT$. M2, @GENE$: p.(E387K). M3, CYP1B1: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(A179fs*18);tmVar:p|FS|A|179||18;HGVS:p.A179fsX18;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0 +"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0 +"@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, @VARIANT$ of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.W482R;tmVar:p|SUB|W|482|R;HGVS:p.W482R;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956,1 + Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the @GENE$ gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the HNF1A variant was present in the mother (Figure 1B).,8306687,HNF1A;459,GCK;55440,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0 +"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and @VARIANT$, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,p.R170W;tmVar:p|SUB|R|170|W;HGVS:p.R170W;VariantGroup:59;CorrespondingGene:1805,0 +"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ @VARIANT$, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0 +"Because charged residues are important for proteins trafficking, the @VARIANT$ may result in accumulation of the Cx31 protein in intracellular compartments such as the Golgi apparatus or in other sites such as the endoplasmic reticulum or lysosomes. The A194T substitution might cause conformational changes within the @GENE$ molecule or affect the ability of Cx31 to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and @VARIANT$ in @GENE$ as well as F193C, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment.",2737700,Cx31;7338,Cx26;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,A197S;tmVar:p|SUB|A|197|S;HGVS:p.A197S;VariantGroup:3;CorrespondingGene:2706;RS#:777236559,0 +" The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0 +"A complete loss of this trans-activational activity was noted for the proteins with missense mutations located in the LBD (@VARIANT$ and p.Asp364Tyr), the SF1 @VARIANT$, as well as both frame-shift mutations assayed (p.Arg89Glyfs*17 and p.Leu209Cysfs*87) (Figure 3). Intriguingly, a nonsense SF1 variant (p.[Pro210Gln;Tyr211*]) seemed to retain a low level of activity (Figure 3). A similar pattern was seen with the SRY/SF1 transfected cells; however, the magnitude of activation was in general lower than that of the SOX9/SF1 transfection (Figure 3). All the @GENE$ variants identified in our DSD patients showed reduced transactivation activity in vitro when co-transfected with SRY or @GENE$. This suggests that the reason these variants are pathogenic is because they result in a dramatic reduction or loss of SF1 transactivation activity in these patients.",5765430,SF1;138518,SOX9;294,p.His310Asp;tmVar:p|SUB|H|310|D;HGVS:p.H310D;VariantGroup:4;CorrespondingGene:6662;RS#:780987236;CA#:8739053,p.47_54del;tmVar:p|DEL|47_54|;HGVS:p.47_54del;VariantGroup:30;CorrespondingGene:2516,0 +"Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of @GENE$ @VARIANT$ increased, which thus lead to a reduction of structural stability.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +" Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus lead to a reduction of structural stability. However, SCN5A @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d). The MFE of @GENE$ p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure. RNA secondary structural prediction. (a, b) Compared with wild-type KCNH2, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus led to a reduction of structural stability.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0 +"Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +" Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"Given the reported normal function of @GENE$ L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0 +"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0 +"RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,GJB3;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Among sensorineural hearing loss patients EVA or the Pendred syndrome patients, a considerable number of patients carry one copy of the mutation on the @GENE$ gene, therefore a compromised pendrin regulatory machinery may be involved in the pathogenesis of the syndrome. To further analyze the role of EphA2 in Pendred syndrome, direct sequencing of the EPHA2 gene in 40 Japanese hearing loss patients with EVA carrying mono-allelic mutation of SLC26A4 were examined. While mutation of ~70 genes causing hearing loss were previously identified as a human nonsyndromic deafness gene, they were not identified in these patients. On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), @GENE$: c.1532C>T (@VARIANT$) (Fig. 6a, b). These EPHA2 mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of SLC26A4 was previously reported.",7067772,SLC26A4;20132,EPHA2;20929,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,0 +"M2, @GENE$: p.(E387K). M3, CYP1B1: @VARIANT$. M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0 +"These two individuals were heterozygous carriers of @VARIANT$ mutation in ABCC6 and p.V255M in GGCX. Since heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. In this case, haploinsufficiency of the carboxylase activity and reduced ABCC6 functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (p.R1141X) and the @GENE$ gene (@VARIANT$) yet did not display any cutaneous findings are not clear.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS. The novel @GENE$ @VARIANT$ mutation substitutes the hydrophobic methionine168 for an arginine (p.Met168Arg) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1.",8621929,WNT10A;22525,LRP6;1747,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,0 +"Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"M3, @GENE$: @VARIANT$. M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0 +"Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,CAPN11;21392,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0 +"To investigate possible oligogenic inheritance involving FOXC2 or @GENE$ and @GENE$, we also analyzed FOXC2 and PITX2 variants in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare FOXC2 variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: @VARIANT$, p.(H395N); and PITX2: @VARIANT$, p.(P179T)) have not been previously identified.",6338360,PITX2;55454,CYP1B1;68035,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +"Therefore, we may speculate that the functional defect of @GENE$-@VARIANT$ could be compromised conductance. Interestingly, it has been reported that the KCNH2-p.C66G variant, located in the PAS domain, reaches the cell surface, but it remains in the immature form and is non-conducting. On the contrary, the functionality of the KCNQ1-p.R583H channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), @GENE$ (c.46C>G; @VARIANT$) and USH2A (c.9921T>G).",3125325,MYO7A;219,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,1 +"Moreover, similar truncations in the highly homologous DUOX2 [p.Q686*, p.R701*, @VARIANT$;(IVS19-2A>C), p.S965fsX994] are associated with CH or severely impaired H2O2-generating activity in vitro. The @VARIANT$ mutation would be predicted to generate a nonfunctional DUOX1 enzyme, and its digenic inheritance alongside the homozygous @GENE$ p.R434* will likely result in complete absence of functional DUOX isoenzyme in our patients. It has been speculated that @GENE$ upregulation in the context of DUOX2 loss of function may at least partially compensate for defective H2O2 production.",5587079,DUOX2;9689,DUOX1;68136,p.(G418fsX482);tmVar:p|FS|G|418||482;HGVS:p.G418fsX482;VariantGroup:2;CorrespondingGene:50506,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0 +"Three variants in three genes were rare, including the @GENE$ gene mutation [@VARIANT$], a novel heterozygous missense variant [c.1801G > A; p.(@VARIANT$)] in the SEMA7A gene (NM_001146029), as well as a splice site variation in the @GENE$ gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,PROKR2;16368,PLXNA1;56426,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0 +"The genotypes of SLC20A2 (NM_001257180.2: @VARIANT$, p.His596Arg) and PDGFRB (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the @GENE$ protein (c.229C>T; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0 +"Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,SCN5A;22738,KCNH2;201,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0 +"Pedigree and sequence chromatograms of the patient with the @VARIANT$ in MYO7A and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,1 +"The c.1787A>G (@VARIANT$) mutation of @GENE$ has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The c.317G>C (p.Arg106Pro) variant of @GENE$, a rare single nucleotide polymorphism (SNP, @VARIANT$), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (@VARIANT$;[=]) (p.Arg80Cys) in the @GENE$ gene. The GNRHR frameshift mutation was identified in two different families and has not been reported before. It consists of an 11 base-pair deletion (@VARIANT$), and if translated, would be expected to result in a truncated protein due to a premature termination codon (p.Phe313Metfs*3).",5527354,GNRHR;350,PROKR2;16368,c.[238C > T];tmVar:c|SUB|C|238|T;HGVS:c.238C>T;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,c.937_947delTTTTTAAACCC;tmVar:c|DEL|937_947|TTTTTAAACCC;HGVS:c.937_947delTTTTTAAACCC;VariantGroup:7;CorrespondingGene:2798,0 +"There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0 + DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0 +"In addition, we found an elevated frequency (8%) of heterozygous and rare @GENE$ variants in the group of CG cases who were known to carry @GENE$ glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, @VARIANT$) have not been previously identified.",6338360,PITX2;55454,CYP1B1;68035,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0 +"(A) In addition to @VARIANT$ in @GENE$, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus.",4998745,GJB2;2975,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0 +" Aberrant regulation of pathogenic forms of @GENE$ via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of @GENE$ with mutated pendrin. myc-pendrin A372V, @VARIANT$, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected.",7067772,pendrin;20132,EphA2;20929,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0 +"c, d Immunoprecipitation of @GENE$ with mutated @GENE$. Immunocomplex of myc-pendrin L117F, @VARIANT$ and @VARIANT$ was not affected.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0 +"Nevertheless, the @VARIANT$ variant has also been considered a benign variant, due to its association with close to normal life expectancy (Tripathi et al., 2011). Recently, Gifford et al., identified three missense variants in @GENE$ (@VARIANT$), @GENE$ (Leu387Phe), and NKX2-5 (Ala119Ser) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MKL2;40917,MYH7;68044,p.Ile736Thr;tmVar:p|SUB|I|736|T;HGVS:p.I736T;VariantGroup:1;CorrespondingGene:4625;RS#:727503261(Expired),Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496,0 +"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS.",8739608,LAMA2;37306,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757,0 +" Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"Mutations in @GENE$ and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0 +" In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0 +"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,MYOD1;7857,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0 +"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,gap junction protein beta 3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"The two variants chr18:77170979 G>A for @GENE$ and chr1:@VARIANT$ for @GENE$ lead to novel missense variants, p.R222Q and @VARIANT$ respectively.",5611365,NFATC1;32336,OBSCN;70869,228462101 G>A;tmVar:c|SUB|G|228462101|A;HGVS:c.228462101G>A;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +II: 1 carried the digenic heterozygous mutations of @GENE$ @VARIANT$ and SCN5A @VARIANT$. I: 1 and II: 2 were heterozygous for @GENE$ p.R1865H.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,1 +" Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits. FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-@GENE$ Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type @GENE$ and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"The @VARIANT$ mutation in the @GENE$ gene segregated with the LVNC phenotype in the examined family. It was also found in one unrelated patient affected by LVNC, confirming a causative role in cardiomyopathy. The @VARIANT$ mutation in the @GENE$ gene, a key component of the basal lamina of muscle fibers, was found only in the proband, suggesting a role in CFTD.",3695851,MYH7B;66117,ITGA7;37592,R890C;tmVar:p|SUB|R|890|C;HGVS:p.R890C;VariantGroup:4;CorrespondingGene:57644;RS#:186471205,E882K;tmVar:p|SUB|E|882|K;HGVS:p.E882K;VariantGroup:1;CorrespondingGene:3679;RS#:144983062;CA#:147560,1 +"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in @GENE$, ANOS1, DCC, @GENE$, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,DUSP6;55621,PLXNA1;56426,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0 +"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,MYO7A;219,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1 +"The mother and son reported by Beijers et al. were heterozygous for @GENE$ @VARIANT$ and @GENE$ @VARIANT$, but the G31D substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/).",4090307,HNF1A;459,HNF4A;395,G31D;tmVar:p|SUB|G|31|D;HGVS:p.G31D;VariantGroup:4;CorrespondingGene:6927;RS#:137853247;CA#:124487,H214Y;tmVar:p|SUB|H|214|Y;HGVS:p.H214Y;VariantGroup:5;CorrespondingGene:3172,1 +"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), @GENE$: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0 +" In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to @GENE$-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-@GENE$ complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, @VARIANT$ (p.Glu631Ter), in EGFR (table 1).",6161649,Smad1;21196,Smad4;31310,p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765,c.1891G>T;tmVar:c|SUB|G|1891|T;HGVS:c.1891G>T;VariantGroup:8;RS#:909905659,0 +"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1 +"Mutations affecting these regions have also been reported in @GENE$ underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in Cx26 as well as @VARIANT$, @VARIANT$ and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (@GENE$, Cx31, and Cx32) suggested that the EC2 and TM4 domains are important to the function of the Cx31 protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear.",2737700,Cx32;137,Cx26;2975,F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706,S198F;tmVar:p|SUB|S|198|F;HGVS:p.S198F;VariantGroup:14;CorrespondingGene:2705,0 +"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0 +"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, @VARIANT$ (c.475A > G p. S159G) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,rs3135932;tmVar:rs3135932;VariantGroup:0;CorrespondingGene:3587;RS#:3135932,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"No mutations in @GENE$, @GENE$, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC5A5;37311,TPO;461,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0 +"According to earlier studies, @GENE$ variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious.",6707335,KIF5A;55861,SPG11;41614,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0 +"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0 +Pedigree and sequence chromatograms of the patient with the @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$ mutations.,3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,1 +"This patient with the @VARIANT$ @GENE$ missense mutation also had a hemizygous KAL1 deletion of the completely conserved @VARIANT$ within the whey-acidic-protein (WAP) domain that forms a disulphide bridge with Cys134 of @GENE$ (Figure S1C,D).",3888818,NELF;10648,anosmin-1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,Cys163;tmVar:p|Allele|C|163;VariantGroup:9;CorrespondingGene:3730,0 +"Four genes (including @GENE$, ZFHX3, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and AGXT2-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"These results suggest an important role of @GENE$ as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of @GENE$. Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected.",7067772,ephrin-B2;3019,ephrin-A1;3262,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).,4293318,VAPB;36163,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0 +"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::@GENE$ (p.A115P), @GENE$ (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,CYP1B1;68035,TEK;397,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0 +"Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A4;20071,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0 +"On the other hand, mutant GFP-@GENE$ A115P and @VARIANT$ showed perturbed interaction with HA-TEK. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of @GENE$ (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010,0 +@GENE$ @VARIANT$ but not @GENE$-gamma @VARIANT$ causes renal defects in Drosophila The fly kidney is composed of garland and pericardial nephrocytes (Fig 6A) that perform the filtration of the hemolymph and Malpighian tubules that function as excretory tubes.,5973622,KAT2B;20834,adducin;22758,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,0 +"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein. A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,alsin;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0 +"Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,TRPV4;11003,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"In order to evaluate the likelihood of @GENE$ and @GENE$ to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients). Using these filtering settings, no variants in OPTN or TBK1 were detected in any of our control datasets which emphasizes that the presence of rare double hits in our FTLD-TDP cohort is unlikely to have occurred by chance alone. Comparison of sequence traces of OPTN exon 8 (harboring the @VARIANT$ mutation) in gDNA and mRNA prepared from cerebellar cortex of case A showed the absence of mutant RNA (T-allele) suggesting the degradation of mutant RNA by nonsense mediated decay (Figure 1c). A similar analysis of OPTN exon 14 (harboring the @VARIANT$) mutation showed significantly reduced amounts of the wild-type (C-allele) in the cDNA sequence suggesting that the missense variant was inherited in trans with respect to the OPTN nonsense mutation (Figure 1c).",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0 +"Pathogenic effects of GBE1 D413N and @GENE$ @VARIANT$ variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ @VARIANT$ variant in MH.",6072915,NDUFS8;1867,RYR1;68069,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,0 +"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). A compound heterozygous TEK mutation (p.E103D and p.E300G) was also observed in 1 family (PCG38). However, the remaining 20 PCG cases harboring a single heterozygous TEK mutation did not carry any additional mutation in the other 35 adult and childhood glaucoma-associated genes (Supplementary Fig. 1; Supplementary Table 1). The co-occurrence of heterozygous @GENE$ and CYP1B1 mutations as seen in our PCG cases were not observed in additional sets of POAG, ARS, Aniridia, and Peter's Anomaly patients.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0 +"She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the @GENE$ locus (Figure 4B). The @VARIANT$ residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C).",4998745,DFNB1;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Two potential disease-causing mutations were identified: (d) @GENE$: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) @GENE$ missense mutation c.1559G>A/@VARIANT$. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (ENAM and LAMA3) mutations.",6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,1 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,LQT2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0 +Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/@GENE$ @VARIANT$ mutations are shown.,5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1 +" Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a @VARIANT$ (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b).",2900916,GGCX;639,VKORC1;11416,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,valine by methionine at position 255;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0 +"(A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0 +"Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (rs144901249) genes.",6180278,COL6A3;37917,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0 +"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (@VARIANT$, p.G505D). A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H).",6098846,TG;2430,DUOXA2;57037,c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370,c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341,1 +"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the @GENE$/TACI C104R mutation.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0 +"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Missense and non-sense were the most frequent variants in both genes, followed by frameshift in @GENE$ and by splicing and frameshift in @GENE$. Six variants in PKD1 occurred de-novo, three of which were not previously described: c.3236del p.(Asp1079Alafs*25), @VARIANT$ p.(Glu2954*), and @VARIANT$. One de-novo and novel variant was also detected in PKD2: c.992G>A p.(Cys331Tyr).",7224062,PKD1;250,PKD2;20104,c.8860G>T;tmVar:c|SUB|G|8860|T;HGVS:c.8860G>T;VariantGroup:46;CorrespondingGene:5310,c.9201+1G>A;tmVar:c|SUB|G|9201+1|A;HGVS:c.9201+1G>A;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,0 +"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1 +"Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, R127W (@VARIANT$) and a heterozygous frameshift mutation in exon 4 of @GENE$, P291fsinsC (@VARIANT$).",4090307,HNF4A;395,HNF1A;459,c.379C>T;tmVar:c|SUB|C|379|T;HGVS:c.379C>T;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,1 +"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0 +"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,UNC13B;31376,SPTBN4;11879,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0 +"Note that subject II:1 in family PCG-133 was diagnosed at the age of 3 months and carried the de novo @VARIANT$ PITX2 variant, whereas his brother, who did not carry this variant, was diagnosed at the age of 10 years. The proband in family PCG-139 also carried a rare PITX2 variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, @GENE$: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: p.(A188T).",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0 +"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, @GENE$ @VARIANT$ (p.Leu10Met) and @GENE$ c.742C > T (@VARIANT$).",7463850,GRIN2A;645,PLXNB2;66630,c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903,p.Arg248Cys;tmVar:p|SUB|R|248|C;HGVS:p.R248C;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0 +"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, @VARIANT$ in @GENE$ and @VARIANT$ in S100A3, and one novel variant in @GENE$, were identified.",6637284,SETDB1;32157,S100A13;7523,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0 +"SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for @GENE$ and KCNH2 mutations. KCNH2 p.307_308del and SCN5A @VARIANT$ of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus lead to a reduction of structural stability.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0 +"Patient P0418 carries a nonsense mutation in @GENE$ (@VARIANT$) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation.",3125325,USH2A;66151,MYO7A;219,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,1 +" Cardiac Phenotype: A FOXC1/@GENE$ Genetic Interaction The cardiac phenotype in the indexed-family is divided into two: a mild VSD not requiring any intervention and a severe TOF-like phenotype that required major intervention (Figure 1). We sought that differential variants inherited from the father would contribute to this differential expressivity of the ARS phenotype within the three affected children in this family: two with a cardiac phenotype and the third with only glaucoma. Interestingly, we unravel two novel missense mutations in @GENE$ (@VARIANT$) and NFATC1 (@VARIANT$) that are predicted to be damaging (Table 4).",5611365,NFATC1;32336,OBSCN;70869,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +" A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,1 +"For example, two variants in proband P15, @VARIANT$ in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,0 +"Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (c.1514G>A, p.G505D). A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H).",6098846,TG;2430,DUOXA2;57037,c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753,c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341,0 +"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.,5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0 +"To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0 +"Moreover, the presence of other variants (@GENE$-@VARIANT$, @GENE$-@VARIANT$, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,1 +"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in OPTN and TBK1 and noted that case A carrying the @VARIANT$ nonsense variant in OPTN, is compound heterozygote for mutations in OPTN as it also carries the rare variant p.Ala481Val (NM_001008211.1:@VARIANT$) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34). In order to evaluate the likelihood of @GENE$ and @GENE$ to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients).",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,c.1442C>T;tmVar:c|SUB|C|1442|T;HGVS:c.1442C>T;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0 +"All of them had confirmed hypogonadotropic hypogonadism and anosmia or hyposmia, and some already harbored a mutation in one of the five KS genes we had previously analyzed, specifically, in @GENE$ (13 patients), FGFR1 (30 patients), FGF8 (3 patients), PROKR2 (30 patients), or PROK2 (12 patients). Nonsynonymous mutations in @GENE$ were found in 24 patients (20 males and 4 females), all in heterozygous state (Table 1). They consist of a frameshifting deletion of 14 nucleotides (c.del1613_1626; p.D538fsX31), and seven different missense mutations (@VARIANT$, p.N153S, p.I400V, p.V435I, @VARIANT$, p.R730Q, p.R733H) that affect evolutionarily conserved aminoacid residues located in different domains of the protein (Figure 3).",3426548,KAL1;55445,SEMA3A;31358,p.R66W;tmVar:p|SUB|R|66|W;HGVS:p.R66W;VariantGroup:4;CorrespondingGene:10371;RS#:143241978,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,0 +"Three SNPs in @GENE$ (@VARIANT$, rs543573, and rs2296871) were in perfect linkage disequilibrium and were considered to be one signal represented by rs2296871. We included only ALS subjects of European ancestry and compared to controls of European ancestry from ESP6500 and the 1000 Genomes Project. SPLINTER-predicted allele frequencies were used for common variants that were not confirmed by genotyping in ALS subjects. Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (rs3739927 and rs882709 in SETX, and @VARIANT$ in @GENE$).",4293318,SETX;41003,EWSR1;136069,rs1183768;tmVar:rs1183768;VariantGroup:64;CorrespondingGene:23064;RS#:1183768,rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143,0 +"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"These phenomenon indicate that the mutated @GENE$-@VARIANT$ (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-c.1103C>T (@VARIANT$) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and @GENE$-@VARIANT$ (p.R583H) were introduced into @GENE$ and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNQ1;85014,KCNH2;201,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0 +"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,CDON;22996,CCDC88C;18903,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0 +" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0 +"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,MYO7A;219,USH2A;66151,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0 +"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes. ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/GJB3, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"c.235delC was recently reported to manifest a dynamic range of SNHL and a slightly milder audiologic phenotype compared with other @GENE$ variants in Koreans. Detection of mutations in MYO15A and @GENE$ in group I are relatively common in East Asian populations, including Koreans, indicating that application of panel sequencing covering the genes prioritized based on the ethnicity-specific prevalence would be effective for identifying GJB2 single heterozygotes with severe to profound SNHL in Koreans. For the family SH60 with a most likely genetic etiology but without a clear result after TES, whole exome sequencing can be used for definitive molecular diagnosis. This family SH60 segregates prelingual or perilingual severe to profound SNHL, likely in an autosomal dominant fashion, although prelingual SNHL of SH60-136 was caused by autosomal recessive mutations in other deafness genes (Figure 3). Further segregation analyses of the two variants (p.R143W and p.D771N) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both @VARIANT$ of GJB2 and @VARIANT$ of WFS1 as a molecular etiology of SH60-136.",4998745,GJB2;2975,TMC1;23670,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0 +"The proband in family PCG-139 also carried a rare @GENE$ variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, @GENE$: @VARIANT$. M3, CYP1B1: p.(E173*).",6338360,PITX2;55454,CYP1B1;68035,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,0 +"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0 +"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0 +"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0 +"Here, we found that @GENE$ A372V, @VARIANT$, Q446R, and G672E did not bind to EphA2. Given the fact that loss of EphA2 disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation. Multiple types of ephrin-A are expressed in the inner ear during development, meanwhile inner ear epithelial cell specific Efnb2 KO mice exhibit EVA-like malformation. While the function of ephrin-A5 in the inner ear was investigated, no reports have shown that any ephrin-A single KO mice show inner ear malformation. These observations suggest an indispensable role of @GENE$ in the morphology of the inner ear.",7067772,pendrin;20132,ephrin-B2;3019,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0 +"Notably, our study has revealed one case of likely oligogenic inheritance for USH1, involving @GENE$ and USH1G, and possibly USH2A. Three cases of digenic inheritance of USH1 have been reported so far, all caused by mutations in @GENE$ and PCDH15, in agreement with the contribution of cadherin-23 and protocadherin-15 to the hair bundle transient lateral links and tip-links. The pathogenicity of the @VARIANT$ mutation in CDH23 is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (@VARIANT$) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention.",3125325,MYO7A;219,CDH23;11142,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217,0 +"In contrast to FGF inhibition, overexpression of IL17RD attenuates the degradation of epidermal growth factor recepter (@GENE$) and enhances downstream MAPK signalling (figure 3). In patient AVM457, a de novo heterozygous missense variant c.3355G>A (@VARIANT$) with a robust deleterious damaging predictions (SIFT=0.1, PolyPhen2=0.99, GERP++=4.33, CADD=29.3) was identified in PREX2 (table 1). PREX2 activates PI3K signalling via inhibition of phosphatase and tensin homolog (PTEN), and both germline and mosaic PTEN variants are associated with AVMs. In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating @GENE$ signalling.",6161649,EGFR;74545,BMP;55955,p.Ala1119Thr;tmVar:p|SUB|A|1119|T;HGVS:p.A1119T;VariantGroup:5;CorrespondingGene:80243;RS#:1212415588,p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765,0 +"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB6;4936,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,PROKR2;16368,DDB1 and CUL4 associated factor 17;80067;1642,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0 +"The patient carried a heterozygous variant of unknown significance in PKHD1, p.(@VARIANT$), defined as likely pathogenic in ClinVar, and a missense variant p.(@VARIANT$) in @GENE$, classified as likely pathogenic. Recessive mutations in PMM2 were reported as associated to hyperinsulinemic hypoglycemia (HI) and @GENE$ (Cabezas et al.,).",7224062,PMM2;257,PKD;55680,His3124Tyr;tmVar:p|SUB|H|3124|Y;HGVS:p.H3124Y;VariantGroup:17;CorrespondingGene:5314,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +" CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MEOX1;3326,TBX6;3389,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0 +"The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +" The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane. @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EPHA2;20929,Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0 +"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1 +"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1 +"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0 +"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the TNFRSF13B/@GENE$ C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 @VARIANT$ gene.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0 +"However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure. RNA secondary structural prediction. (a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A @VARIANT$ showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0 +"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0 +"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,1 +The @GENE$ @VARIANT$ and @GENE$ @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.,5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,1 +" Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1 +"While both @GENE$ variants, p.(Ser127Thr) and p.(@VARIANT$), were inherited from her father, the @GENE$ mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1 +"Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1 +"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1 +"Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,CDON;22996,DCC;21081,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0 +"In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and @VARIANT$ (p.Gln989Leu) in @GENE$ (table 2). @GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAM;74393,DSCAML1;79549,c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,c.2966A>T;tmVar:c|SUB|A|2966|T;HGVS:c.2966A>T;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0 +" Human @GENE$ and KAT2B, were subcloned from human full-length cDNA (ADD3: clone IMAGE: 6649991; KAT2B clone IMAGE: 30333414) into the expression vectors pLentiGIII and PLEX-MCS, respectively. An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and KAT2B. The ADD3 @VARIANT$ and @GENE$ @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.",5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0 +"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"20 The identified @GENE$ (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 @GENE$, 24 and CAPN9. 25 The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,CUX1;22551,TRIP6;37757,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0 +"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Total Serum Ig, clinical score and @GENE$/TACI @VARIANT$ and @GENE$ @VARIANT$ genotype for each family member, as indicated.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T161fsX191;tmVar:p|FS|T|161||191;HGVS:p.T161fsX191;VariantGroup:5;CorrespondingGene:6929,1 +"The ADD3 @VARIANT$ and @GENE$ @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. All constructs were verified by sequencing. ADD3 or KAT2B depleted podocytes were transduced with WT or mutant @GENE$ or KAT2B lentiviral particles, respectively.",5973622,KAT2B;20834,ADD3;40893,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0 +"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0 +"Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged TEK) and GFP-@GENE$ followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-CYP1B1 are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%).",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0 +"KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, @GENE$-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0 +"We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, @VARIANT$, in one of the @VARIANT$ carriers (SH107-225) (Figure 4A). She inherited c.235delC of @GENE$ from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B).",4998745,MITF;4892,GJB2;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0 +"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in @GENE$ were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3). Therefore, the inherited @GENE$ variant and de novo TIMP3 variant could contribute to BAVM via additive effects on the same pathway.",6161649,TIMP3;36322,RASA1;2168,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0 +"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R566L, p.@VARIANT$) vector plasmids and myc-tagged WT or mutant TTC26 (@VARIANT$, p.R50C). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and @GENE$ genes (figure 1).",7279190,FLNB;37480,TTC26;11786,A2282T;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0 +"The pathogenicity of the @VARIANT$ mutation in @GENE$ is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (p.T1868del) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention. Three protocadherin-15 isoforms (CD1-3) that differ in their intracytoplasmic regions have been reported. Already two presumably pathogenic mutations (p.M1853L and p.T1868del) have been found in exon 34 that is specific for CD1. Incidentally, the @VARIANT$ mutation was not only involved in USH1, but has also been found, in homozygous state, in a deaf patient presenting with vestibular arreflexia and without retinitis pigmentosa (C. Bonnet, unpublished). The CD2 isoform(s) of @GENE$ make(s) the transient kinociliary links, whereas the protocadherin-15 isoforms that make transient interstereocilia links and the tip-links are still unknown.",3125325,CDH23;11142,protocadherin-15;23401,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217,0 +"Detection of mutations Screening of the WNT10A, EDA, EDAR, and EDARADD genes was performed by direct sequencing of five PCR fragments for @GENE$, eight PCR fragments for EDA, ten PCR fragments for EDAR, and eight PCR fragments for @GENE$, which cover the entire cDNA including exons and intron-exon junctions of more than 100 base pairs. We compared all primer sequences to the whole-genome assembly in the ENSEMBL database to verify their uniqueness against gene families. Primer sequences are available upon request. Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (p.R171C and @VARIANT$) and two novel EDA mutations (@VARIANT$ and p.I312M) that were identified in this study.",3842385,WNT10A;22525,EDARADD;15430,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0 +"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and c.158-1G>A in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in MYO7A. Another variation, @VARIANT$ in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0 +"A single control also had two mutations, @VARIANT$ in ALS2 and @VARIANT$ in @GENE$. @GENE$ pathogenicity has only been observed in homozygotes, and this individual was heterozygous.",5445258,TARDBP;7221,ALS2;23264,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0 +"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0 +"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB6;4936,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0 +"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0 +"This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2).",6161649,BMP;55955,ENG;92,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB3;7338,GJB2;2975,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0 +"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in MYO7A and @GENE$, and, all the more, the mutations in the three genes (Figure 2).",3125325,MYO7A;219,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0 +"Although the signaling networks between @GENE$ and @GENE$ remain unclear, their common final pathway in regulating potassium ion circulation in the inner ear can be significantly disrupted by the digenic effect of MITF and GJB2 mutations. A subject with Waardenburg syndrome type II (WS2) in a large Chinese population had both MITF and GJB2 mutations in a compound heterozygous state. The profound SNHL in the subject may have been caused by the digenic effect of GJB2 and MITF mutations, although the WS2 phenotype was caused by the MITF mutation. In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in GJB2 and a de novo variant, @VARIANT$ in MITF.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0 +"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0 +"In this family, the evidence-based on the genetic and functional findings indicated that the loss-of-function mutation @GENE$-@VARIANT$ was the detrimental variation, and that the gain-of-function variant @GENE$-@VARIANT$ modulated the phenotype.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1 +"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0 +"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0 +"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ @VARIANT$, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0 +"In addition, the @VARIANT$ (p. Gly194Cys) and @VARIANT$ (p. Gly716Val) variants were identified by the software as harmful. In previous studies, the phenotype of the @GENE$ gene was not completely dominant, and most of the variants were inherited from a normal father or mother. However, most of the patients in our study had de novo variants; one patient inherited the variants from his father, while the other patient inherited the variants from her mother. Two female patients had a frameshift variant of the FGFR1 gene, which showed an infantile uterus and ovary. In the group with a nonreproductive phenotype, variants in the FGFR1 gene were found in one patient with cleft lip and palate, which was consistent with the report of a previous study. Another patient presented with a renal cyst and short stature. Therefore, anosmia, sexual dysplasia, irregular tooth alignment, cleft lip and palate, syndactyly, and renal abnormalities were common phenotypes of IHH patients with FGFR1 gene variants. The @GENE$ gene is located on chromosome 8q12.1 and is autosomal dominant, encoding chromosomal helicase DNA-binding protein 7.",8796337,FGFR1;69065,CHD7;19067,c.580G > T;tmVar:c|SUB|G|580|T;HGVS:c.580G>T;VariantGroup:8;CorrespondingGene:3730;RS#:1064796777,c.2147G > T;tmVar:c|SUB|G|2147|T;HGVS:c.2147G>T;VariantGroup:2;CorrespondingGene:2260,0 +"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX2;9689,DUOX1 and -2;53905;50506,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0 +"In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, FOXC2 variants p.S36S (synonymous) and @VARIANT$ (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and @GENE$-@GENE$ genes.",6338360,FOXC2;21091,AS1;736,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394,0