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stringclasses 689
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|---|---|---|---|---|---|---|
Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of @GENE$ 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.
| 8,739,608
|
LAMA2;37306
|
KCNH2;201
|
c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099
|
p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651
| 0no label
|
DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = @GENE$, 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 GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).
| 4,998,745
|
gap junction protein beta 3;7338
|
gap junction protein beta 6;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
| 0no label
|
Similarly, our results indicate that increased transactivation associated with the @VARIANT$ PITX2 mutation is not related with altered protein stability, protein conformation or subcellular localization. Proline possesses a hydrophobic side chain, whereas threonine side chain has both hydrophilic and hydrophobic functions. 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 p.(A188T) 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, @GENE$ variants p.S36S (synonymous) and @VARIANT$ (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-AS1 genes.
| 6,338,360
|
PITX2;55454
|
FOXC2;21091
|
p.P179T;tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928
|
c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394
| 0no label
|
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/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).
| 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
| 11
|
In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.
| 2,737,700
|
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
| 0no label
|
Direct sequence analysis showing the @VARIANT$ 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).
| 2,737,700
|
Cx31;7338
|
Cx26;2975
|
299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204
|
497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
| 0no label
|
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$, it results in the substitution of @VARIANT$. 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.
| 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
|
Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313
| 11
|
Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) 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.
| 5,953,556
|
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
| 11
|
Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene. Moreover, a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the @GENE$ has also been identified.
| 7,877,624
|
MITF;4892
|
C2orf74;49849
|
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
| 0no label
|
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 @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.
| 7,877,624
|
MITF;4892
|
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
| 0no label
|
Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) 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 LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.
| 6,610,752
|
LQT6;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
| 0no label
|
Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (@VARIANT$, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).
| 8,621,929
|
LRP6;1747
|
WNT10A;22525
|
g.68531T>G;tmVar:g|SUB|T|68531|G;HGVS:g.68531T>G;VariantGroup:11;CorrespondingGene:4040
|
p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313
| 11
|
Notably, proband P05 in family 05 harbored a de novo @GENE$ 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$) and a maternal variant (@GENE$ @VARIANT$).
| 8,152,424
|
FGFR1;69065
|
CCDC88C;18903
|
p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919
|
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
| 0no label
|
The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).
| 3,842,385
|
WNT10A;22525
|
EDA;1896
|
Ile at residue 312 to Met;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
| 0no label
|
Sequence analyses of @GENE$ 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.
| 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.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 0no label
|
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. 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$-@VARIANT$ were previously reported to produce more severe phenotypes when combined with disease-causing alleles.
| 5,578,023
|
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
| 0no label
|
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 arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; @VARIANT$) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts.
| 6,637,284
|
S100A13;7523
|
S100A3;2223
|
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
| 0no label
|
@GENE$ gene might interact with MITF 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$) in the @GENE$ gene and a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the C2orf74 was identified.
| 7,877,624
|
C2orf74;49849
|
MITF;4892
|
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
|
c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263
| 0no label
|
Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
EDN3;88
|
SNAI3;8500
|
p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286
|
c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
| 0no label
|
Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.
| 5,966,321
|
CELSR1;7665
|
DVL3;20928
|
p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181
|
p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763
| 0no label
|
(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.
| 4,998,745
|
DFNB1;2975
|
gap junction protein beta 3;7338
|
p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706
|
p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313
| 0no label
|
Furthermore, these missense mutations were either unreported in the ExAC population database (@VARIANT$, and p.Tyr283His) 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.
| 5,527,354
|
GNRHR;350
|
PROKR2;16368
|
p.Arg139Cys;tmVar:p|SUB|R|139|C;HGVS:p.R139C;VariantGroup:2;CorrespondingGene:2798;RS#:1325732095
|
p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400
| 0no label
|
Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of @VARIANT$ 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 @GENE$/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.
| 4,998,745
|
GJB2;2975
|
gap junction protein beta 3;7338
|
p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251
|
p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706
| 0no label
|
The c.1592G>A (@VARIANT$) @GENE$ 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$) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).
| 6,161,649
|
SCUBE2;36383
|
MAP4K4;7442
|
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
| 0no label
|
17 Although the functional evidence of combined defects in oxidative DNA damage repair genes is still lacking, the coinheritance of @GENE$ and @GENE$ variants in at least three, but likely five cancer cases within one family warrants further mechanistic and clinical studies. The absence of cancer and numerous polyps in nondigenic carriers further substantiates this association. Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of MSH6 @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (KRAS @VARIANT$) was absent in this tumor, which points toward retained MUTYH repair activity.
| 7,689,793
|
MSH6;149
|
MUTYH;8156
|
p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473
|
c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137
| 0no label
|
To further analyze the role of @GENE$ in Pendred syndrome, direct sequencing of the EPHA2 gene in 40 Japanese hearing loss patients with EVA carrying mono-allelic mutation of @GENE$ 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: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).
| 7,067,772
|
EphA2;20929
|
SLC26A4;20132
|
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
|
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 (@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
|
GJB6;4936
|
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
|
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 @GENE$ depleted podocytes were transduced with WT or mutant ADD3 or KAT2B lentiviral particles, respectively.
| 5,973,622
|
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
| 0no label
|
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 @GENE$ frameshift mutation was identified in two different families and has not been reported before. It consists of an 11 base-pair deletion (@VARIANT$), and if translated, would be expected to result in a truncated protein due to a premature termination codon (p.Phe313Metfs*3).
| 5,527,354
|
PROKR2;16368
|
GNRHR;350
|
p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400
|
c.937_947delTTTTTAAACCC;tmVar:c|DEL|937_947|TTTTTAAACCC;HGVS:c.937_947delTTTTTAAACCC;VariantGroup:7;CorrespondingGene:2798
| 0no label
|
The heterozygous p.Arg156Cys (@VARIANT$) 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. 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 EDA and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected.
| 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
|
p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 0no label
|
The @VARIANT$ variant is predicted to be deleterious by four prediction programs and is absent in 13,006 control chromosomes from the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP) and in 672 chromosomes from Middle Eastern persons (including 36 chromosomes from Palestinian persons). OTUD4 encodes a deubiquitinase (Fig. S1 in the Supplementary Appendix). The @VARIANT$ variant is predicted to be deleterious by three of four prediction programs and is found in 2 of the 13,006 chromosomes from the ESP and in none of the 672 chromosomes from Middle Eastern persons. Both @GENE$ and @GENE$ were sequenced in nine affected persons from seven unrelated families.
| 3,738,065
|
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
| 0no label
|
Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (p.M927V) in one patient, (2) DUOX2:@VARIANT$ (p.R1110Q) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.
| 6,098,846
|
DUOX2;9689
|
DUOXA2;57037
|
c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;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
| 0no label
|
Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in @GENE$ (@VARIANT$, p.Pro392Leu) and a heterozygous variant in @GENE$ (c.1070A>G, @VARIANT$).
| 5,868,303
|
SQSTM1;31202
|
TIA1;20692
|
c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866
|
p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407
| 11
|
Notably, proband P05 in family 05 harbored a de novo @GENE$ 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$ p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).
| 8,152,424
|
FGFR1;69065
|
DCC;21081
|
c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260
|
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
| 0no label
|
CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 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
|
(B) The predicted 2D structure of human @GENE$ protein. The @VARIANT$ and G213 residues are in yellow. The 3D structure of @GENE$ 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.
| 3,842,385
|
WNT10A;22525
|
EDA;1896
|
R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555
|
G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
| 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/@VARIANT$, 235delC/A194T and 299delAT/A194T).
| 2,737,700
|
Cx31;7338
|
GJB2;2975
|
299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706
|
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
| 0no label
|
Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the @GENE$ gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the GCK variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).
| 8,306,687
|
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
| 0no label
|
Case A was a compound heterozygote for mutations in @GENE$, carrying the p.Q235* nonsense and @VARIANT$ 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$) in @GENE$. 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.
| 4,470,809
|
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
| 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 @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$/@VARIANT$).
| 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) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (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.
| 8,172,206
|
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
| 0no label
|
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 @VARIANT$ 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)p. Gln91Arg, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.
| 8,152,424
|
CCDC88C;18903
|
FGFR1;69065
|
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
|
c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260
| 11
|
The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of 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.
| 3,842,385
|
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
| 0no label
|
The p.Ile312Met (c.936C>G) mutation in EDA 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 @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 WNT10A mutations at the same locus as that of N2 (Fig. 2B).
| 3,842,385
|
WNT10A;22525
|
EDA;1896
|
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
| 0no label
|
Compared to the Nav1.5 protein properties of wild-type @GENE$, SCN5A p.R1865H slightly increased its molecular weight and aliphatic index but reduced its instability index. Theoretical pI, aliphatic index, and GRAVY were not affected by SCN5A p.R1865H. Amino acids physical and chemical parameter prediction Physical and chemical parameters KCNH2-wild type KCNH2-@VARIANT$ SCN5A-wild type SCN5A-@VARIANT$ Molecular weight 14430.15 14359.07 18856.35 18872.39 Theoretical pI 9.30 9.30 12.10 12.10 Instability index 30.43 30.59 95.32 91.73 Aliphatic index 106.54 106.59 45.00 47.22 GRAVY 0.336 0.325 -0.541 -0.511 Abbreviation: GRAVY, Grand average of hydropathicity. Next, hydrophobicity analyses for wild-type and mutant proteins were performed (Table 4, Figure 5). The changed site (position 307) of @GENE$ p.307_308del was located close to the largest hydrophobic region of the protein (Figure 5a).
| 8,739,608
|
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
| 0no label
|
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$ @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys).
| 8,152,424
|
DCC;21081
|
CCDC88C;18903
|
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
| 0no label
|
Four potential pathogenic variants, including @GENE$ @VARIANT$ (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (NM_000426, c.G2881A), 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).
| 8,739,608
|
SCN5A;22738
|
LAMA2;37306
|
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
| 0no label
|
We also identified a monoallelic change in @GENE$ (c.G680A, p.Arg227Gln, @VARIANT$:G>A) in Patient 11, who also harbored a @VARIANT$ of @GENE$ (Table 3).
| 5,765,430
|
SRD5A2;37292
|
NR5A1;3638
|
rs9332964;tmVar:rs9332964;VariantGroup:0;CorrespondingGene:6716;RS#:9332964
|
single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516
| 11
|
On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), @GENE$: @VARIANT$ (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).
| 7,067,772
|
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
| 0no label
|
Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @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.
| 4,293,318
|
VAPB;36163
|
FUS;2521
|
p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311
|
p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276
| 0no label
|
For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in @GENE$ (DCAF17), were inherited from unaffected father, while @GENE$ 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 @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 @VARIANT$).
| 8,152,424
|
DDB1 and CUL4 associated factor 17;80067;1642
|
DMXL2;41022
|
c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260
|
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
| 0no label
|
The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ 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$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ 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 FUS protein. However, the two rare FUS variants (@VARIANT$ and P106L) 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.
| 6,707,335
|
SPG11;41614
|
ubiquilin-2;81830
|
M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941
|
Y25C;tmVar:p|SUB|Y|25|C;HGVS:p.Y25C;VariantGroup:12;CorrespondingGene:2521;RS#:141516414;CA#:8023442
| 0no label
|
Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.
| 3,426,548
|
PROKR2;16368
|
FGFR1;69065
|
p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481
|
p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730
| 0no label
|
(C) The sequence of the @VARIANT$ 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 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.
| 4,998,745
|
GJB3;7338
|
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
| 0no label
|
These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and @GENE$. 3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, p.Ala754Pro, and @VARIANT$ were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively. Particularly, p.Met168Arg and @VARIANT$ were highly destabilizing, as their DeltaDeltaGs were higher than 1.00 kcal mol-1.
| 8,621,929
|
LRP6;1747
|
WNT10A;22525
|
p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188
|
p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379
| 0no label
|
For example, two variants in proband P15, p. Ala103Val in @GENE$ 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$ @VARIANT$ variants from his unaffected father and mother, respectively.
| 8,152,424
|
PROKR2;16368
|
CDON;22996
|
p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487
|
p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125
| 0no label
|
Our study suggests that the KCNH2-@VARIANT$ 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$-p.R583H, @GENE$-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.
| 5,578,023
|
KCNQ1;85014
|
KCNH2;201
|
p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757
|
p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330
| 0no label
|
In silico analyses (figure 3C) indicated that the @VARIANT$ residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 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 p.R2003H @GENE$ and @VARIANT$ @GENE$ (figure 3D).
| 7,279,190
|
FLNB;37480
|
OFD1;2677
|
R2003;tmVar:R2003;VariantGroup:29;CorrespondingGene:2317
|
p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481
| 0no label
|
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/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).
| 2,737,700
|
GJB3;7338
|
GJB2;2975
|
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
|
299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706
| 0no label
|
The mother and the father were asymptomatic carriers of PKHD1: c.4437_4440delCATA (p.F1479Lfs*20) and @GENE$: c.5935G > A (p.G1979R), respectively (Figure 3). The foetuses in Family 24 and Family 25 appeared to have additional symptoms besides PKD. The couple from Family 24 had undergone abortion three times due to phenotypes similar to those in renal cystic disorders, bladder dysplasia and oligohydramnios. The sample of the third pregnancy was subjected to genetic testing using WES plus Sanger sequencing. The compound heterozygous variants of TMEM67: @VARIANT$ (@VARIANT$) and TMEM67: c.579delA (p.G195Dfs*27) were identified and likely agreed with the Meckel Gruber syndrome type 3 (@GENE$, MIM #607316), which segregated from the asymptomatic parents (Figure 3).
| 8,256,360
|
PKHD1;16336
|
MKS3;71886
|
c.637C > T;tmVar:c|SUB|C|637|T;HGVS:c.637C>T;VariantGroup:3;CorrespondingGene:5314;RS#:866575098;CA#:138924774
|
p.R213C;tmVar:p|SUB|R|213|C;HGVS:p.R213C;VariantGroup:3;CorrespondingGene:91147;RS#:866575098
| 0no label
|
We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ 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 @VARIANT$ (0.016) alleles were found in the control population (Table 1).
| 5,953,556
|
CYP1B1;68035
|
TEK;397
|
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
| 0no label
|
Molecular genetic studies A previously described homozygous @GENE$ nonsense mutation (c.1300C>T, @VARIANT$) had initially been identified in P1 and P2, for which their parents and unaffected sibling were heterozygous (Fig. 1). DNA was not available from the deceased sibling. The severity of the CH prompted investigation for an additional genetic mutation using whole-exome sequencing in P1 and P2. In addition to coding regions, significant intronic sequences were covered using this technique, enabling detection of a homozygous essential splice site change in @GENE$ (@VARIANT$), at the intron 14/exon 15 boundary, validated by Sanger sequencing in both cases.
| 5,587,079
|
DUOX2;9689
|
DUOX1;68136
|
p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026
|
c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905
| 11
|
To investigate the role of @GENE$ 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 (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).
| 2,737,700
|
GJB3;7338
|
GJB2;2975
|
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
| 0no label
|
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of @GENE$).
| 3,888,818
|
NELF;10648
|
TACR3;824
|
c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137
|
p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871
| 0no label
|
In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (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).
| 2,737,700
|
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
| 0no label
|
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$-R1193Q showed the ERS phenotypes. The female CACNA1C-Q1916R mutation carriers with SCN5A-R1193Q variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the @GENE$-@VARIANT$ mutation (IV-4) showed the ER ECG pattern.
| 5,426,766
|
SCN5A;22738
|
CACNA1C;55484
|
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
| 0no label
|
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 @GENE$ (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 GJB2. The pathogenic potential of the p.T123N variant is controversial. Three variants of USH2A (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208).
| 4,998,745
|
GJB3;7338
|
ANK1;55427
|
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
| 0no label
|
Variants in all known WS candidate genes (@GENE$, @GENE$, 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 TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
EDN3;88
|
EDNRB;89
|
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
|
We have screened 108 @GENE$ 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 @GENE$ are the second mutant allele in these Chinese heterozygous probands. 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).
| 2,737,700
|
GJB2;2975
|
GJB6;4936
|
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
| 0no label
|
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; MYH7:part of the sarcomere, and LAMA4:part of the ECM/signalling component. To our knowledge, this is the first description of digenic mutations in MYH7 and LAMA4. The mutations were inherited from the parents, the mother carrying a @GENE$ mutation and with mild DCM, and a father carrying the @GENE$ variation but with a normal heart at age 29.
| 6,359,299
|
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
| 0no label
|
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB @VARIANT$ and @GENE$ p.R408C with SETX p.I2547T and SETX p.T14I).
| 4,293,318
|
ANG;74385
|
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
|
We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) 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).
| 5,953,556
|
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
| 0no label
|
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 @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).
| 5,887,939
|
SCRIB;44228
|
FZD1;20750
|
c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625
|
c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776
| 0no label
|
Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (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).
| 8,739,608
|
LAMA2;37306
|
KCNH2;201
|
p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099
|
p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757
| 0no label
|
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$) in the @GENE$ gene.
| 6,707,335
|
MATR3;7830
|
DYNC1H1;1053
|
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
| 0no label
|
The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @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.
| 3,842,385
|
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
|
T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896
| 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 c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$).
| 3,888,818
|
NELF;10648
|
TACR3;824
|
p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730
|
c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137
| 0no label
|
The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@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 PDGFRB variant.
| 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
|
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, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).
| 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
|
The @VARIANT$ (c.936C>G) mutation in @GENE$ 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.
| 3,842,385
|
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
| 0no label
|
As mentioned above, some family members carrying heterozygous SCN5A @VARIANT$ mutation showed no evidence of cardiac events or cardiac diseases. The reason may be as follows: First, I:1 and II:2 who carried with the heterozygous @GENE$ p.R1865H presented no clinical syndromes because of incomplete penetrance or delayed onset. Moreover, gain-of-function mutation of SCN5A commonly induced LQTS, while loss-of-function mutation of SCN5A 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 p.R1865H 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.
| 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
|
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 @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.
| 3,842,385
|
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
| 0no label
|
To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.
| 7,067,772
|
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
| 0no label
|
The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI C104R mutations. Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations are shown.
| 5,671,988
|
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
| 0no label
|
In subject 10035, a deleterious variant within the @GENE$ (Chr2) locus was identified in IMP4 (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 @GENE$ (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.
| 6,081,235
|
DYT21;100885773
|
ARHGEF19;17710
|
rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628
|
rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415
| 0no label
|
For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 @VARIANT$ 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$ 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$).
| 8,152,424
|
DCAF17;65979
|
FGFR1;69065
|
p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930
|
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
| 0no label
|
Both homozygous and compound heterozygous variants in the @GENE$ 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 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.
| 6,707,335
|
ALS2;23264
|
DYNC1H1;1053
|
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
| 0no label
|
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 @GENE$-@VARIANT$ and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles.
| 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.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162
| 0no label
|
Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.
| 2,737,700
|
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
| 0no label
|
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; p.Cys163del of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).
| 3,888,818
|
KAL1;55445
|
NELF;10648
|
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
|
Functional testing of three @GENE$ 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 @VARIANT$ 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.
| 5,893,726
|
GATA4;1551
|
CYP17;73875
|
p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748
|
p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463
| 0no label
|
Results We identified the digenic heterozygous mutations of @GENE$ @VARIANT$ (NM_001204798, @VARIANT$) and @GENE$ p.R1865H (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest.
| 8,739,608
|
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
| 0no label
|
Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged @GENE$) and GFP-CYP1B1 followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-CYP1B1 are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ 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 E229 K as compared to WT proteins (Fig. 2).
| 5,953,556
|
TEK;397
|
CYP1B1;68035
|
E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183
|
G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449
| 0no label
|
Conclusions Our study demonstrates that a novel mutation, @GENE$-@VARIANT$, dramatically impairs the IKr repolarizing current, whereas @GENE$-@VARIANT$, although previously reported to cause LQTS, probably exerts sub-pathogenic defects that are more consistent with a modifier allele.
| 5,578,023
|
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
| 11
|
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
SNAI2;31127
|
TYRO3;4585
|
c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
|
c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@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.
| 2,737,700
|
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
| 0no label
|
Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.
| 5,578,023
|
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
| 11
|
Conservation analyses at the mutant sites of @GENE$ 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. 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$. Except II: 1, other family members did not carry with the KCNH2 mutation RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type @GENE$ (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b).
| 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
|
Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, 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$, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of @GENE$, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).
| 5,966,321
|
CELSR1;7665
|
SCRIB;44228
|
p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763
|
p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663
| 0no label
|
(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (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.
| 8,172,206
|
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
| 0no label
|
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