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2 classes
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 @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.
8,152,424
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
0no label
On the other hand, mutant GFP-@GENE$ A115P and @VARIANT$ showed perturbed interaction with HA-@GENE$. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d).
5,953,556
CYP1B1;68035
TEK;397
R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016
E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340
0no label
In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified @GENE$ variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, SRY, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and @VARIANT$ activated the @GENE$ promoter similar to wt.
5,893,726
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
0no label
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. 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.
6,707,335
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
0no label
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/@VARIANT$, 235delC/A194T and @VARIANT$/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.
2,737,700
Cx26;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
0no label
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 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. 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.
6,707,335
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
0no label
Our results indicate that the novel KCNH2-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, @GENE$-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.
5,578,023
KCNQ1;85014
KCNH2;201
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
0no label
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 @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).
3,842,385
EDA;1896
WNT10A;22525
Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896
Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
11
None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis. We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: @VARIANT$, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: 179264731T/C, rs10277; Ch5: 179264915G/T, rs1065154 ].
5,868,303
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
179260153C/T;tmVar:c|SUB|C|179260153|T;HGVS:c.179260153C>T;VariantGroup:9;CorrespondingGene:8878;RS#:4935;CA#:3600710
0no label
In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and @GENE$ (@VARIANT$).
3,125,325
USH1G;56113
USH2A;66151
c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353
c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382
11
WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (@VARIANT$;p.R85C) inherited from an unaffected mother, and a @GENE$ (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.
5,505,202
WDR11;41229
EMX1;55799
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
0no label
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 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$ p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).
8,152,424
DCC;21081
CCDC88C;18903
p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
0no label
Three rare missense variants (R2034Q, L2118V, and @VARIANT$) 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 (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.
6,707,335
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
0no label
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 S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.
7,067,772
pendrin;20132
EphA2;20929
Phe335 to Leu;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
0no label
In Family F, the GJB2/@VARIANT$ 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 @VARIANT$/@GENE$, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k).
2,737,700
GJB3;7338
GJB2;2975
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
0no label
CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and @VARIANT$ (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$/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (@GENE$, AD2) and helix-loop-helix (HLH) domains are shown.
5,671,988
TNFRSF13B;49320
AD1;56379
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
0no label
Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.
7,877,624
EDNRB;89
PAX3;22494
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
0no label
The @VARIANT$ (p.His596Arg) 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).
8,172,206
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
0no label
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 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.
3,842,385
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
0no label
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 @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.
3,842,385
WNT10A;22525
EDA;1896
c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313
p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655
0no label
The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. "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$, this leads to the substitution of Gly at residue 213 to Ser.
3,842,385
EDA;1896
WNT10A;22525
termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896
c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
0no label
In those samples, no mutation was detected on the second allele either in @GENE$-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 (@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).
2,737,700
Cx26;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
0no label
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 PTK7 c.1925C > G (@VARIANT$) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.
5,966,321
CELSR1;7665
SCRIB;44228
p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292
p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763
0no label
On the other hand, two missense mutations of the EPHA2 gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), @GENE$: @VARIANT$ (p.T511M) (Fig. 6a, b).
7,067,772
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.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151
0no label
Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
7,877,624
EDN3;88
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
0no label
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 @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).
7,279,190
FLNB;37480
TTC26;11786
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
0no label
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$ (@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$).
6,567,512
BBS2;12122
BBS6;10318
c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583
Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386
0no label
Moreover, patients carrying a LAMA4 @VARIANT$ 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 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$) and @GENE$ (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated.
6,359,299
MYH7;68044
MYBPC3;215
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
0no label
Two different GJB3 mutations (N166S 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$/@VARIANT$). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.
2,737,700
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
0no label
(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, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.
4,998,745
GJB6;4936
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
0no label
Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.
2,737,700
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
0no label
Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @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.
6,081,235
HS1BP3;10980
DNAH17;72102
p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346
p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342
0no label
It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.
5,725,008
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
0no label
He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; rs7673715) @VARIANT$; p.N409S and @GENE$ (MIM 600509; NM_000352.4; @VARIANT$) c.3989-9G>A mutations.
5,505,202
GBA;68040
ABCC8;68048
c.1226A>G;tmVar:c|SUB|A|1226|G;HGVS:c.1226A>G;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767
rs151344623;tmVar:rs151344623;VariantGroup:4;CorrespondingGene:6833;RS#:151344623
11
We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).
6,567,512
BBS1;11641
BBS2;12122
c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582
c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212
0no label
Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ 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.
4,293,318
DCTN1;3011
VAPB;36163
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
0no label
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 @VARIANT$ and @GENE$ p.T14I).
4,293,318
TAF15;131088
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
0no label
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 @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 (@VARIANT$ and G4290R) in the DYNC1H1 gene.
6,707,335
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
0no label
Proband 17 inherited CHD7 @VARIANT$ and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant.
8,152,424
CDON;22996
FGFR1;69065
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
0no label
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, @VARIANT$ and F355L was not affected.
7,067,772
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
0no label
The most common mutation was p.R1110Q (@GENE$: c.3329G>A), which was found in 5 patients, accounting for 11% of all the cases. Of the 3 novel variants in DUOX2, @VARIANT$ 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 (SLC26A4, 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.
7,248,516
DUOX2;9689
TPO;461
p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506
p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991
0no label
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$, rs544478083 in @GENE$ (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).
8,172,206
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
0no label
These findings support the importance of @GENE$ 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.
6,359,299
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
0no label
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 KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of @GENE$).
3,888,818
NELF;10648
TACR3;824
c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012
p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730
0no label
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ @VARIANT$ and @GENE$ p.R408C with SETX p.I2547T and SETX p.T14I).
4,293,318
VAPB;36163
TAF15;131088
p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953
p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276
0no label
(E) The @GENE$ 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 EDA and c.511C>T in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.
3,842,385
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
0no label
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$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.
6,610,752
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
0no label
The mutations of KCNH2 p.307_308del and @GENE$ @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 SCN5A and @GENE$ protein were highly conserved (Figure 2). Therefore, KCNH2 @VARIANT$ was considered as de novo mutation in II: 1 (Figure 1a and Figure 3).
8,739,608
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
0no label
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 @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.
3,842,385
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
0no label
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$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(Ser123Thr), and a second variant in @GENE$, p.(@VARIANT$).
7,224,062
PKD1;250
PKD2;20104
Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907
Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303
0no label
In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in @GENE$ (c.3925G > A, @VARIANT$) and a known DCM mutation in @GENE$ (c.2770G > A; @VARIANT$).
6,359,299
LAMA4;37604
MYH7;68044
p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057
p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034
11
In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development. Moreover, GATA4 functionally interacts with NR5A1 in Sertoli cell cultures to positively regulate the expression of AMH, and therefore, it has been reported that mutations in NR5A1 may cause 46,XY DSD due to lack of interaction with @GENE$. No gonadal involvement is mostly detected in families with GATA4 mutations and isolated CHD, possibly because some of the variants retain some DNA-binding activity and exhibit different degrees of transcriptional activation on gonadal promoters and thus, remain able to synergize with NR5A1. In the present study, the @VARIANT$ mutation was found in a patient with a complex CHD, genital ambiguity, and persistent Mullerian ducts, which led to female gender assignment. We propose that cysteine to arginine change in position 238 of GATA4 lacks activity to bind DNA reducing the transactivation of @GENE$ critically.
5,893,726
GATA;6699
AMH;68060
p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463
p.Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626
0no label
A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).
7,463,850
EHMT1;11698
MFSD8;115814
p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656
p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496
11
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$; NM_033056: c.3101G > A; @VARIANT$] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).
6,053,831
PCDH15;23401
USH1G;56113
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
0no label
Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.
7,026,993
GFI1;3854
MYO6;56417
p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872
p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203
11
Three rare missense variants (R2034Q, @VARIANT$, 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 @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.
6,707,335
SPG11;41614
UBQLN2;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
0no label
Her mother with @VARIANT$ in COL4A5 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. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.
6,565,573
COL4A3;68033
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
0no label
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 @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).
2,737,700
Cx26;2975
Cx31;7338
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
0no label
Three rare missense variants (R2034Q, @VARIANT$, 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 (@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.
6,707,335
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
0no label
Molecular genetic studies A previously described homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*) had initially been identified in P1 and P2, for which their parents and unaffected sibling were heterozygous (Fig. 1). DNA was not available from the deceased sibling. The severity of the CH prompted investigation for an additional genetic mutation using whole-exome sequencing in P1 and P2. In addition to coding regions, significant intronic sequences were covered using this technique, enabling detection of a homozygous essential splice site change in @GENE$ (@VARIANT$), at the intron 14/exon 15 boundary, validated by Sanger sequencing in both cases.
5,587,079
DUOX2;9689
DUOX1;68136
c.1300C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636
c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905
11
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
7,877,624
MITF;4892
TYRO3;4585
p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
0no label
Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), 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,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.
6,081,235
DNAH17;72102
UNC13B;31376
p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211
c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615
0no label
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with @GENE$ p.M170I and TAF15 @VARIANT$ with SETX @VARIANT$ and SETX p.T14I).
4,293,318
ANG;74385
VAPB;36163
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
0no label
Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), @GENE$ (@VARIANT$), and DES (rs144901249) genes.
6,180,278
RYR1;68069
CAPN3;52
rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558
rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448
0no label
In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and c.2966A>T (@VARIANT$) in @GENE$ (table 2). @GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.
6,161,649
DSCAM;74393
DSCAML1;79549
p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588
p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588
0no label
Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.
2,737,700
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
0no label
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, 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).
2,737,700
GJB2;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
0no label
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 p.307_308del 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 SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ 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).
8,739,608
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
0no label
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$, c.238_239dupC in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.
3,125,325
MYO7A;219
USH2A;66151
c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997
c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060
0no label
The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ 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. 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$, S275N) were detected.
6,707,335
CCNF;1335
ALS2;23264
G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568
P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187
0no label
Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: 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.
4,293,318
DCTN1;3011
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
0no label
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, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, 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$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.
6,081,235
ATP2A3;69131
VPS13C;41188
p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011
c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137
0no label
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (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).
3,888,818
KAL1;55445
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
0no label
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
7,877,624
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
0no label
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$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
7,877,624
SOX10;5055
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
0no label
II: 1 carried the digenic heterozygous mutations of @GENE$ @VARIANT$ and @GENE$ p.R1865H. I: 1 and II: 2 were heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry KCNH2 mutation.
8,739,608
KCNH2;201
SCN5A;22738
p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757
p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651
0no label
Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @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; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.
7,877,624
MITF;4892
PAX3;22494
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
0no label
Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-@GENE$ @VARIANT$, respectively, was significantly diminished.
5,953,556
CYP1B1;68035
TEK;397
A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052
Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010
0no label
CSS161458 had a heterozygous splicing variant @VARIANT$ 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 @GENE$ has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).
7,549,550
RIPPLY1;138181
MYOD1;7857
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
0no label
These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ 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 ABCC6 gene (p.R1141X) and the GGCX 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. 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.
2,900,916
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
0no label
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 @VARIANT$ of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).
2,737,700
Cx31;7338
GJB2;2975
299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
0no label
We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@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.(Cys412Phe).
6,567,512
BBS1;11641
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
0no label
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 @VARIANT$, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ 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 E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-TEK.
5,953,556
TEK;397
CYP1B1;68035
Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010
A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052
0no label
Based on these findings, we conclude that, unlike LQTS-associated mutations, the @GENE$-@VARIANT$ variant does not severely affect the function of the channel. 2.3.2. @GENE$-p.C108Y Exhibits a Dominant-Negative Loss-of-Function Heterologous expression studies demonstrated that KCNH2-@VARIANT$ is a non-functional channel (Figure 4A).
5,578,023
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
0no label
This patient with the @VARIANT$ NELF 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 anosmin-1 (Figure S1C,D). Unilateral renal agenesis in this patient is likely related to this deleterious KAL1 mutation. The third KS male was heterozygous for both @GENE$ and @GENE$ nonsense mutations.
3,888,818
NELF;10648
TACR3;824
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
0no label
Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, 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.
7,877,624
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
0no label
Functional characterisation of AIS-associated FLNB variants According to alignment to the @GENE$ protein domain, most of the AIS-associated FLNB variants are located within immunoglobulin-like filamin repeat regions, some of which belong to the domain of interaction with @GENE$ (figure 2A). Of note, @VARIANT$ is located within the actin-binding domain of FLNB. We transfected wild-type or mutant plasmids into HEK293T cells and found that some FLNB variants (including p.M1803L, p.S2503G and p.T2166M; online supplementary figure 1) resulted in cytoplasmic focal accumulation, and some other FLNB variants (including p.R566L, @VARIANT$, p.S2503G, p.R199Q and p.R2003H; online supplementary figure 2) altered actin dynamics (online supplementary figures 1 and 2).
7,279,190
FLNB;37480
FLNA;1119
p.R199Q;tmVar:p|SUB|R|199|Q;HGVS:p.R199Q;VariantGroup:0;CorrespondingGene:79989;RS#:1175244100
p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246
0no label
Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and @GENE$ (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.
7,026,993
GFI1;3854
MYO6;56417
p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872
p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203
0no label
Other family members who have inherited @GENE$ @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 @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2.
5,671,988
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
0no label
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 USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.
3,125,325
MYO7A;219
USH2A;66151
c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415
c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060
0no label
Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @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 @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).
2,737,700
Cx31;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
0no label
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
7,877,624
SNAI2;31127
TYRO3;4585
p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286
c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
0no label
We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and 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$).
2,737,700
GJB2;2975
GJB3;7338
299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
0no label
Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ 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 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 SETX p.I2547T and @GENE$ p.T14I).
4,293,318
ANG;74385
SETX;41003
p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311
p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390
0no label
The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected. These mutations were not found in his father's genome, but because his mother's DNA sample was unavailable, the origin of the mutant alleles was not clear (Fig. 2F). All novel mutations that were identified in this study were not found in the normal controls. Protein structure analysis The results of protein structure analyses of @GENE$ are shown in Figure 3.
3,842,385
EDA;1896
WNT10A;22525
p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657
p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
0no label
Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-@VARIANT$, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.
5,578,023
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
0no label
Future studies will focus on determining how double homozygous mutations in @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$) result in increased intracellular pro-COL1A1 levels and increased pro-COLA1 secretion.
4,853,519
SEC23A;4642
MAN1B1;5230
1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384
1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197
11
(E) The EDA mutation @VARIANT$ and @GENE$ mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in @GENE$ and @VARIANT$ in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.
3,842,385
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
c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
0no label
We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.
5,953,556
TEK;397
CYP1B1;68035
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
0no label
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$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
7,877,624
EDN3;88
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
0no label