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| gene1
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stringclasses 392
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stringclasses 689
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|---|---|---|---|---|---|---|
In addition, 2 genes presented variants in 3 patients: MAML3 (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and @GENE$ variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).
| 6,726,737
|
NOTCH1;32049
|
MAML3;41284
|
p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322
|
c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269
| 0no label
|
Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.
| 4,470,809
|
TBK1;22742
|
OPTN;11085
|
p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520
|
p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889
| 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$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) 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.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
| 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 ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.
| 6,707,335
|
CCNF;1335
|
MATR3;7830
|
G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568
|
P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187
| 0no label
|
Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
MITF;4892
|
PAX3;22494
|
p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286
|
c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
| 0no label
|
The c.229C>T (@VARIANT$) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2. Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, S100A13 and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.
| 6,637,284
|
S100A13;7523
|
S100A3;2223
|
p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284
|
c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284
| 0no label
|
Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The c.1787A>G (@VARIANT$) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).
| 8,172,206
|
SLC20A2;68531
|
PDGFRB;1960
|
c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083
|
p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575
| 0no label
|
To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ 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 @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).
| 2,737,700
|
Cx31;7338
|
GJB2;2975
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
|
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
| 0no label
|
Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
EDNRB;89
|
SOX10;5055
|
p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286
|
c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 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$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.
| 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
|
c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
| 0no label
|
Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ c.1200G>C (@VARIANT$) and @GENE$ c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family.
| 4,853,519
|
SEC23A;4642
|
MAN1B1;5230
|
p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384
|
p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197
| 11
|
Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-@GENE$ @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished.
| 5,953,556
|
CYP1B1;68035
|
TEK;397
|
E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183
|
E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873
| 0no label
|
DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.
| 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
|
Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).
| 5,887,939
|
CELSR1;7665
|
FZD6;2617
|
c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776
|
c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776
| 0no label
|
In the individual carrying the @VARIANT$ @GENE$ variant, an additional novel alteration (@VARIANT$) was detected in the @GENE$ gene.
| 6,707,335
|
NEFH;40755
|
GRN;1577
|
P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372
|
C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519
| 11
|
A concomitant variant (@VARIANT$, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be "gain-of-function" and associated with long QT syndrome (LQTS). Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (@VARIANT$, p.Q1916R) in CACNA1C.
| 5,426,766
|
CACNA1C;55484
|
SCN5A;22738
|
p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287
|
c.5747A>G;tmVar:c|SUB|A|5747|G;HGVS:c.5747A>G;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963
| 0no label
|
CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.
| 7,549,550
|
MEOX1;3326
|
MYOD1;7857
|
c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491
|
p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682
| 0no label
|
Its numerous domains allow @GENE$ to serve as a frame for multiprotein complexes and regulator of ubiquitinated protein turnover. SQSTM1 mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.
| 5,868,303
|
SQSTM1;31202
|
TIA1;20692
|
c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired)
|
p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407
| 0no label
|
Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
| 7,877,624
|
EDNRB;89
|
TYRO3;4585
|
c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
|
p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, @VARIANT$), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (WNT10A c.637G>A, rs147680216) in EAS.
| 8,621,929
|
WNT10A;22525
|
LRP6;1747
|
c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313
|
rs2302686;tmVar:rs2302686;VariantGroup:2;CorrespondingGene:4040;RS#:2302686
| 0no label
|
(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.
| 3,975,370
|
IL10RA;1196
|
NOD2;11156
|
c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322
|
c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322
| 0no label
|
(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).
| 8,172,206
|
SLC20A2;68531
|
PDGFRB;1960
|
p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575
|
rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083
| 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 (@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
|
GJB2;2975
|
Cx31;7338
|
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
| 0no label
|
These phenomenon indicate that the mutated @GENE$-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-@VARIANT$ (p.Ala338Val) variant impaired the catabolism of ADMA in EA.
| 5,725,008
|
SCAP;8160
|
AGXT2;12887
|
p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937
|
c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745
| 0no label
|
Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6. A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in MFSD8.
| 7,463,850
|
SLC9A6;55971
|
EHMT1;11698
|
p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857
|
c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496
| 0no label
|
The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.
| 6,707,335
|
ALS2;23264
|
MATR3;7830
|
G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568
|
S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809
| 0no label
|
The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and @GENE$ genes.
| 3,842,385
|
EDA;1896
|
WNT10A;22525
|
Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
|
c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
| 0no label
|
Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (AD1, @GENE$) and helix-loop-helix (HLH) domains are shown.
| 5,671,988
|
TNFRSF13B;49320
|
AD2;30951
|
c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387
|
T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929
| 0no label
|
Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family. Hence, priority should be given to identifying the @GENE$ T168fsX191 mutation for preimplantation genetic diagnosis and/or chorionic villus sampling.
| 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
|
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).
| 3,888,818
|
NELF;10648
|
KAL1;55445
|
c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012
|
p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871
| 0no label
|
Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).
| 2,737,700
|
GJB3;7338
|
GJB2;2975
|
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
| 0no label
|
(E) The @GENE$ mutation c.466C>T and WNT10A mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ 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.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313
|
c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657
| 0no label
|
The novel truncated variant in @GENE$ was not found in our "in-house" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (@VARIANT$) variant in @GENE$ and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.
| 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
|
c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284
| 0no label
|
Among the 18 variants, three missense variations, the new @GENE$ mutation (@VARIANT$) and the known @GENE$ missense variants (@VARIANT$ and G351R), caught our attention: we hypothesized that these three variants might together contribute to an increased risk of developing early onset IBD.
| 3,975,370
|
NOD2;11156
|
IL10RA;1196
|
K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561
|
S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561
| 11
|
Therefore, in this study, @GENE$ p.R1865H may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction. CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and SCN5A @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.
| 8,739,608
|
SCN5A;22738
|
KCNH2;201
|
p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757
|
p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651
| 0no label
|
Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$).
| 6,610,752
|
KCNH2;201
|
LQT6;71688
|
c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221
|
p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493
| 0no label
|
DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.
| 8,172,206
|
PDGFRB;1960
|
SLC20A2;68531
|
p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575
|
p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083
| 0no label
|
Additionally, a novel variant (@VARIANT$) in the 5' untranslated region of the FUS gene was also detected. As the screening of untranslated regions was not in the scope of our research, we did not examine it further. No SOD1 and TARDBP gene variants were found in this cohort. We would like to point out that 37 of the analyzed samples were overlapping samples from a previous study and were known to be negative for SOD1 and @GENE$ mutations. Still, based on earlier results, one would expect to detect SOD1 variants in the further 70 samples. Variants Detected in Minor ALS Genes By focusing on the analysis of minor ALS genes, 33 variants (31 missense and 2 splicing) were detected in 26 genes corresponding to 29 patients (27.1% of all patients, Supplementary Table 2 ). No patients were identified as being homozygous for any of the detected variants. A patient was carrying two novel variants (T2583I and @VARIANT$) in the @GENE$ gene; both variants localized in the motor domain of the protein.
| 6,707,335
|
TARDBP;7221
|
DYNC1H1;1053
|
c.-25C > T;tmVar:c|SUB|C|-25|T;HGVS:c.-25C>T;VariantGroup:38;CorrespondingGene:2521
|
G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051
| 0no label
|
GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (@VARIANT$), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).
| 4,998,745
|
DFNB1;2975
|
TMC1;23670
|
c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943
|
rs121908073;tmVar:rs121908073;VariantGroup:11;CorrespondingGene:117531;RS#:121908073
| 0no label
|
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and TAF15 p.R408C with SETX @VARIANT$ and @GENE$ p.T14I).
| 4,293,318
|
VAPB;36163
|
SETX;41003
|
p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276
|
p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108
| 0no label
|
No mutations in SLC5A5, @GENE$, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.
| 6,098,846
|
TPO;461
|
IYD;12352
|
c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155
|
p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391
| 0no label
|
Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.
| 6,371,743
|
NRXN1;21005
|
NRXN2;86984
|
p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143
|
c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001
| 11
|
In our study, @VARIANT$(p. Arg631*) and c.1267C > T(@VARIANT$) were the two reported variants, while c.1525delA(p. Ser509fs) and c.1524del A(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of @GENE$ gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function. @GENE$ (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2.
| 8,796,337
|
KAl1;55445
|
Prokineticin-2;9268
|
c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223
|
p. Arg423*;tmVar:p|SUB|R|423|*;HGVS:p.R423*;VariantGroup:7;CorrespondingGene:3730
| 0no label
|
Two unaffected subjects, SH60-137 and SH60-139, also carried @VARIANT$ in WFS1. This indicates that neither p.R143W in GJB2 nor p.D771N in WFS1 contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject. @GENE$ = gap junction protein beta 2, SNHL = sensorineural hearing loss, WFS1 = wolfram syndrome 1. Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, p.R341C, in one of the @VARIANT$ carriers (SH107-225) (Figure 4A).
| 4,998,745
|
GJB2;2975
|
MITF;4892
|
p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681
|
c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943
| 0no label
|
Moreover, the MAF of @GENE$-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-@VARIANT$ were much larger (0.187 and 0.352, respectively).
| 5,578,023
|
KCNQ1;85014
|
KCNE1;3753
|
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
| 0no label
|
Sequence alterations were detected in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.
| 6,180,278
|
RYR1;68069
|
DES;56469
|
rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558
|
rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249
| 0no label
|
We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.
| 5,966,321
|
SCRIB;44228
|
CELSR1;7665
|
c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292
|
p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763
| 0no label
|
The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors.
| 3,842,385
|
EDA;1896
|
WNT10A;22525
|
p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655
|
Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313
| 11
|
RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).
| 2,737,700
|
Cx26;2975
|
Cx31;7338
|
asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
| 11
|
To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/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
|
RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).
| 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
| 11
|
Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).
| 2,737,700
|
GJB2;2975
|
GJB3;7338
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
|
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
| 11
|
A male (ID104) was found to have a heterozygous missense variant @VARIANT$ (p.Lys330Met) in EHMT1 and a missense variant @VARIANT$ (p.Leu593Val) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases.
| 7,463,850
|
SLC9A6;55971
|
EHMT1;11698
|
c.989A > T;tmVar:c|SUB|A|989|T;HGVS:c.989A>T;VariantGroup:1;CorrespondingGene:79813;RS#:764291502;CA#:5375151
|
c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465
| 0no label
|
In this family, the patient (II: 1) with digenic heterozygous mutations of KCNH2 p.307_308del and SCN5A @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without KCNH2 @VARIANT$ showed normal QT intervals and cardiac function. The changed site of KCNH2 p.307_308 was highly conserved across most species, suggesting p.307_308 of @GENE$ protein playing a significant role in function. The result indicated that the novel genetic background, KCNH2 p.307_308del, may affect and even induce the phenotype of LQTS. The predictions of the RNA secondary structure and physical-chemical parameters showed KCNH2 p.307_308del affected the single-stranded RNA folding, and subsequently and significantly weaken the hydrophobicity of mutant amino acid residues, which indicated that KCNH2 mutation probably played a dominant hereditary role in the occurrence of LQTS in this proband. SCN5A gene is located in chromosome 3p22.2, encoding the alpha subunit of the voltage-gated sodium channel (@GENE$) in human cardiomyocytes (Li et al.,).
| 8,739,608
|
KCNH2;201
|
Nav1.5;22738
|
p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651
|
p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757
| 0no label
|
Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.
| 3,426,548
|
KAL1;55445
|
PROKR2;16368
|
p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071
|
p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278
| 0no label
|
We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).
| 2,737,700
|
GJB2;2975
|
GJB6;4936
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
|
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
| 0no label
|
Digenic inheritances of @GENE$/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.
| 4,998,745
|
GJB2;2975
|
GJB3;7338
|
c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943
|
p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251
| 0no label
|
In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (c.46C>G; @VARIANT$) and @GENE$ (c.9921T>G).
| 3,125,325
|
USH1G;56113
|
USH2A;66151
|
c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647
|
p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353
| 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 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.
| 4,998,745
|
gap junction protein beta 2;2975
|
GJB3;7338
|
p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251
|
p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313
| 0no label
|
These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (@VARIANT$), a novel nucleotide deletion (@VARIANT$; p.E2135fsX31), and six missense mutations, four of which (p.R1189W, p.R1379P, p.D2639G, and p.R3043W) had not been previously reported.
| 3,125,325
|
harmonin;77476
|
CDH23;11142
|
c.6050-9G>A;tmVar:c|SUB|G|6050-9|A;HGVS:c.6050-9G>A;VariantGroup:172;CorrespondingGene:64072;RS#:367928692;CA#:261794
|
c.6404_6405delAG;tmVar:c|DEL|6404_6405|AG;HGVS:c.6404_6405delAG;VariantGroup:207;CorrespondingGene:65217
| 0no label
|
This genetic synergism is also supported by the potential digenic inheritance of LRP6 and @GENE$ mutations in Family 4. The proband, who had @GENE$ p.(@VARIANT$), p.(Ser127Thr), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.
| 8,621,929
|
WNT10A;22525
|
LRP6;1747
|
Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188
|
Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379
| 0no label
|
Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, @GENE$, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, FGF10, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with @GENE$, which also is connected with RIPK4.
| 6,726,737
|
FGF10;3284
|
PTPN11;2122
|
p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322
|
p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269
| 0no label
|
To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, DFNB3, and @GENE$, respectively. Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES.
| 4,998,745
|
DFNB16;15401
|
WFS1;4380
|
p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234
|
p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681
| 0no label
|
This analysis indicated that the CAPN3 variant c.1663G>A (rs138172448), which results in a @VARIANT$ change, and the DES gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient.
| 6,180,278
|
CAPN3;52
|
DES;56469
|
p.Val555Ile;tmVar:p|SUB|V|555|I;HGVS:p.V555I;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461
|
c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118
| 11
|
However, significantly more pro-COL1A1 was secreted in fibroblasts with heterozygous mutations in both SEC23A and @GENE$ (P < 0.05, ANOVA), when compared with wild type (Supplemental Fig. S7). Surprisingly, mutant fibroblasts showed levels of intracellular and secreted pro-COL1A1 comparable with those of wild-type cells. Our data indicate that a normal level of MAN1B1 is required to prevent secretion of abnormally folded pro-COL1A1. These data also indicate that an alternate pathway is used for quality control of pro-COL1A1 when MAN1B1 alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in @GENE$, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet.
| 4,853,519
|
MAN1B1;5230
|
SEC23A;4642
|
1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384
|
1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197
| 0no label
|
On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. On the contrary, in the mother, some other factors, including unknown genetic modifiers, could counteract the functional impairment of mutant channels, thereby protecting the asymptomatic @GENE$-@VARIANT$ mutation-positive subject from arrhythmia susceptibility.
| 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
|
He had no mutations in @GENE$, FGF8, FGFR1, PROK2, PROKR2, TAC3, @GENE$, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to @VARIANT$ ;p.Thr478Ala from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease.
| 3,888,818
|
CHD7;19067
|
KAL1;55445
|
c.1432A>G;tmVar:c|SUB|A|1432|G;HGVS:c.1432A>G;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174
|
p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218
| 0no label
|
However, none of these signs were evident from metabolic work of the patient with @GENE$ L718F, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and @GENE$ @VARIANT$ variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the RYR1 p.T4823 M variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with CACNA1S @VARIANT$, previously reported in a single MHS subject.
| 6,072,915
|
PHKA1;1981
|
NDUFS8;1867
|
I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290
|
p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268
| 0no label
|
At the molecular level, @GENE$ mediates cell-cell adhesion by regulating PI3K/@GENE$ signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (@VARIANT$) was identified in IL17RD (table 1).
| 6,161,649
|
N-cadherin;20424
|
Akt;3785
|
c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588
|
p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588
| 0no label
|
(C) The sequence of the @VARIANT$ 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, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.
| 4,998,745
|
GJB2;2975
|
MITF;4892
|
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 @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 (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and 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
|
C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519
| 0no label
|
Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @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
|
EDNRB;89
|
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
|
We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).
| 5,953,556
|
CYP1B1;68035
|
TEK;397
|
p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052
|
I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918
| 0no label
|
In patient AVM558, the de novo heterozygous missense variant c.1694G>A (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo. In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/@GENE$ signalling (figure 3). In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (p.Gly226Ser) was identified in IL17RD (table 1).
| 6,161,649
|
BMP;55955
|
Akt;3785
|
c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730
|
c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588
| 0no label
|
The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly).
| 7,224,062
|
PKD2;20104
|
PKD1;250
|
Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907
|
Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716
| 11
|
Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.
| 6,707,335
|
SPG11;41614
|
UBQLN2;81830
|
L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152
|
M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941
| 0no label
|
Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene @GENE$ were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.
| 5,953,556
|
TEK;397
|
CYP1B1;68035
|
p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873
|
p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052
| 0no label
|
Myopathy With @GENE$ and @GENE$ Variants: Clinical and Pathological Features Objective The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Patients and methods Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (@VARIANT$, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, @VARIANT$).
| 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
|
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 @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.
| 3,842,385
|
WNT10A;22525
|
EDA;1896
|
Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
|
c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
| 0no label
|
The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.
| 3,842,385
|
WNT10A;22525
|
EDA;1896
|
Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
|
c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 0no label
|
Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).
| 3,125,325
|
CDH23;11142
|
MYO7A;219
|
p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764
|
c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647
| 0no label
|
This analysis indicated that the @GENE$ variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the @GENE$ gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging.
| 6,180,278
|
CAPN3;52
|
DES;56469
|
rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448
|
c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118
| 0no label
|
On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).
| 7,067,772
|
EPHA2;20929
|
SLC26A4;20132
|
p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403
|
p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151
| 0no label
|
Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.
| 6,081,235
|
HS1BP3;10980
|
DNAH17;72102
|
c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773
|
c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011
| 0no label
|
Moreover, this @GENE$ variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages. Digenic inheritances of GJB2/MITF and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.
| 4,998,745
|
MITF;4892
|
gap junction protein beta 6;4936
|
c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943
|
p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251
| 0no label
|
Mutations in @GENE$ and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.
| 6,371,743
|
NRXN1;21005
|
NRXN2;86984
|
c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143
|
p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001
| 0no label
|
In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/GJB3, while the mother is heterozygous for the @GENE$/@VARIANT$ (Fig. 1k).
| 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
|
299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204
| 0no label
|
LIMITATIONS Our study was performed only in the statistical field on @GENE$ p.307_308del and SCN5A p.R1865H by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ increases the risk of the early-onset LQTS and sinoatrial node dysfunction.
| 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
|
The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation 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
|
Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
|
C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 0no label
|
Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and @GENE$ genes. The results demonstrated the presence of two missense mutations in @GENE$. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b).
| 2,900,916
|
VKORC1;11416
|
GGCX;639
|
c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442
|
p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957
| 0no label
|
Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
| 7,877,624
|
MITF;4892
|
TYRO3;4585
|
p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286
|
p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
| 7,877,624
|
EDN3;88
|
MITF;4892
|
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
|
p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Sequence analyses of EDA and @GENE$ 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. (B) The @GENE$ mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.
| 3,842,385
|
WNT10A;22525
|
EDA;1896
|
c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
|
c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 0no label
|
DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.
| 8,172,206
|
SLC20A2;68531
|
PDGFRB;1960
|
p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083
|
p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575
| 0no label
|
A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. ATP2A3 is highly expressed in cerebellar Purkinje cells (Allen Brain Atlas) and is a member of the P-type ATPase superfamily that includes the gene (@GENE$) causally associated with rapid-onset dystonia-Parkinsonism (DYT12).
| 6,081,235
|
NOS2;55473
|
ATP1A3;113729
|
c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122
|
p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126
| 0no label
|
Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.
| 2,737,700
|
Cx31;7338
|
GJB2;2975
|
G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
| 0no label
|
GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (@VARIANT$) (rs121908073), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).
| 4,998,745
|
DFNB1;2975
|
TMC1;23670
|
c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943
|
c.100C>T;tmVar:c|SUB|C|100|T;HGVS:c.100C>T;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002
| 0no label
|
The most common mutation was @VARIANT$ (@GENE$: c.3329G>A), which was found in 5 patients, accounting for 11% of all the cases. Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and p.E389K were missense mutations located in the peroxidase-like domain (Fig. S3A). A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, DUOXA2 and TPO). A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).
| 7,248,516
|
DUOX2;9689
|
SLC26A4;20132
|
p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:12;CorrespondingGene:50506;RS#:368488511;CA#:7537915
|
p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885
| 0no label
|
Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
EDNRB;89
|
SNAI3;8500
|
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
|
c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Three rare missense variants (R2034Q, @VARIANT$, 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 @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.
| 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
|
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