sentence
stringlengths 61
1.36k
| pmcid
int32 162k
8.8M
| gene1
stringclasses 381
values | gene2
stringclasses 392
values | variant1
stringclasses 689
values | variant2
stringclasses 654
values | label
class label 2
classes |
|---|---|---|---|---|---|---|
Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.
| 6,081,235
|
HS1BP3;10980
|
MRPL15;32210
|
p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342
|
c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137
| 0no label
|
On the other hand, EphA2 overexpression did not affect localization of @VARIANT$. The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f).
| 7,067,772
|
pendrin;20132
|
ephrin-B2;3019
|
G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423
|
S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985
| 0no label
|
Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).
| 2,737,700
|
GJB2;2975
|
GJB3;7338
|
A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
| 0no label
|
Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a p.D771N variant in @GENE$ (WFS1) (NM_001145853) according to TES. However, neither p.R143W in GJB2 nor @VARIANT$ in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).
| 4,998,745
|
GJB2;2975
|
Wolfram syndrome 1;4380
|
p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234
|
p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681
| 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/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.
| 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
|
Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).
| 5,887,939
|
SCRIB;44228
|
CELSR2;1078
|
c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776
|
c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818
| 0no label
|
Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.
| 6,565,573
|
COL4A5;133559
|
COL4A4;20071
|
c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287
|
Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204
| 0no label
|
One patient had a novel de novo variant of @GENE$ (@VARIANT$, p. Ser509fs) and a hot spot variant of @GENE$ (c.533G > C, @VARIANT$) simultaneously.
| 8,796,337
|
KAl1;55445
|
PROKR2;16368
|
c.1524delA;tmVar:c|DEL|1524|A;HGVS:c.1524delA;VariantGroup:17;CorrespondingGene:3730
|
p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917
| 11
|
CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2). DISCUSSION In this study, we performed exome sequencing on 584 patients with @GENE$ and without a molecular diagnosis.
| 7,549,550
|
RIPPLY1;138181
|
CS;56073
|
c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129
|
c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444
| 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 @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.
| 5,578,023
|
KCNQ1;85014
|
KCNE1;3753
|
p.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
|
The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/@GENE$ @VARIANT$ mutations are shown.
| 5,671,988
|
TCF3;2408
|
TACI;49320
|
T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929
|
C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387
| 0no label
|
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 @VARIANT$ with SETX p.I2547T and @GENE$ p.T14I).
| 4,293,318
|
VAPB;36163
|
SETX;41003
|
p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953
|
p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127
| 0no label
|
Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in OPTN and TBK1 and noted that case A carrying the @VARIANT$ nonsense variant in OPTN, is compound heterozygote for mutations in OPTN as it also carries the rare variant @VARIANT$ (NM_001008211.1:c.1442C>T) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34). In order to evaluate the likelihood of @GENE$ and @GENE$ to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients).
| 4,470,809
|
OPTN;11085
|
TBK1;22742
|
p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110
|
p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970
| 0no label
|
In fact, skin biopsies from the proband and her sister depicted preponderance of under-carboxylated @GENE$, when examined by immunohistochemistry using specific antibodies that distinguish the fully carboxylated and under-carboxylated forms of the protein. Furthermore, assay of total ucMGP in plasma, which has been recently suggested to serve as a biomarker of cardiovascular calcification, was reduced in patients with skin findings, apparently reflecting tissue mineralization. An intriguing observation in our family was the presence of PXE-like cutaneous features, with profound mineralization, in the proband's mother and aunt. These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ and @VARIANT$ in GGCX.
| 2,900,916
|
MGP;693
|
ABCC6;55559
|
p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115
|
p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957
| 0no label
|
We identified four genetic variants (@GENE$-p.R583H, KCNH2-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$) in an LQTS family.
| 5,578,023
|
KCNQ1;85014
|
KCNE1;3753
|
p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757
|
p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330
| 0no label
|
The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA. "S2" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.
| 3,842,385
|
EDA;1896
|
WNT10A;22525
|
T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896
|
c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313
| 0no label
|
M2, @GENE$: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: @VARIANT$. M5, @GENE$: @VARIANT$. Arrows show the index cases.
| 6,338,360
|
CYP1B1;68035
|
PITX2;55454
|
p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928
|
p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139
| 0no label
|
The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.
| 3,842,385
|
EDA;1896
|
WNT10A;22525
|
termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896
|
Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 11
|
In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.
| 3,125,325
|
MYO7A;219
|
USH2A;66151
|
c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647
|
c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382
| 11
|
The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and 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.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 0no label
|
(A) Patient with homozygous variants in both @GENE$ and @GENE$ genes. NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and @VARIANT$ (R284C) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation.
| 6,292,381
|
ANO5;100071
|
SGCA;9
|
p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516
|
c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431
| 11
|
In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and c.1524del A(@VARIANT$) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of KAl1 gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function. @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. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed PROK2/@GENE$ variants, which was significantly higher than the 9% in the Caucasian population.
| 8,796,337
|
Prokineticin-2;9268
|
PROKR2;16368
|
c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223
|
p. Ser509fs;tmVar:p|FS|S|509||;HGVS:p.S509fsX;VariantGroup:19;CorrespondingGene:3730
| 0no label
|
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).
| 3,888,818
|
NELF;10648
|
KAL1;55445
|
p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730
|
c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137
| 0no label
|
A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, @VARIANT$ and p.S1067L, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).
| 6,098,846
|
DUOXA2;57037
|
DUOX2;9689
|
c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341
|
p.H678R;tmVar:p|SUB|H|678|R;HGVS:p.H678R;VariantGroup:21;CorrespondingGene:50506;RS#:57659670;CA#:7538401
| 0no label
|
The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.
| 6,637,284
|
SETDB1;32157
|
S100A13;7523
|
rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706
|
c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284
| 0no label
|
Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).
| 8,152,424
|
CDON;22996
|
CCDC88C;18903
|
p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125
|
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
| 0no label
|
Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ @GENE$ proteins, respectively (figure 2D, E).
| 7,279,190
|
TTC26;11786
|
FLNB;37480
|
p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058
|
p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280
| 0no label
|
We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).
| 5,953,556
|
TEK;397
|
CYP1B1;68035
|
p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052
|
E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873
| 0no label
|
On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations.
| 8,446,458
|
PROKR2;16368
|
DUSP6;55621
|
p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674
|
p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072
| 0no label
|
We identified four genetic variants (@GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and @GENE$-@VARIANT$, using the whole-cell patch clamp technique.
| 5,578,023
|
KCNQ1;85014
|
KCNH2;201
|
p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304
|
p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757
| 0no label
|
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
PAX3;22494
|
SOX10;5055
|
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
|
c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (@VARIANT$) in the MITF gene. Moreover, a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the C2orf74 has also been identified. The C2orf74 is an uncharacterized gene present in the linked region detected by DominantMapper. Variants in @GENE$ and C2orf74 follows autosomal dominant segregation with the phenotype, however, the variant in C2orf74 is incompletely penetrant. We proposed a digenic inheritance of variants as an underlying cause of WS2 in this family. Introduction Waardenburg syndrome (WS) is a group of rare hereditary disorders. It is characterized by pigmentary defects of hair (white forelock), eyes (heterochromia iridis) and skin (hypo-pigmented skin), abnormalities in the inner ear (bilateral sensorineural hearing impairment), and dystopia canthorum (lateral displacement of the inner canthi of the eyes). WS syndrome has been categorized into four major types (@GENE$, WS2, WS3 and WS4).
| 7,877,624
|
MITF;4892
|
WS1;22494
|
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
|
c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263
| 0no label
|
The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS. MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.
| 6,707,335
|
ALS2;23264
|
MATR3;7830
|
S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809
|
P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187
| 0no label
|
To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).
| 2,737,700
|
Cx31;7338
|
GJB2;2975
|
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
|
299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706
| 0no label
|
Recently, Gifford et al., identified three missense variants in MKL2 (@VARIANT$), @GENE$ (Leu387Phe), and @GENE$ (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).
| 7,057,083
|
MYH7;68044
|
NKX2-5;1482;4824
|
Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496
|
Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058
| 0no label
|
Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).
| 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
|
Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I).
| 4,293,318
|
VAPB;36163
|
TAF15;131088
|
p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276
|
p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127
| 0no label
|
A new pathogenic variant in @GENE$ affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3.
| 6,567,512
|
BBS2;12122
|
BBS7;12395
|
p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583
|
c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212
| 0no label
|
18 , 19 This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20 The identified @GENE$ (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21 Additional gene reportedly linked to tumorigenesis include RYR3, 22 EBNA1BP2, 23 TRIP6, 24 and CAPN9. 25 The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.
| 7,689,793
|
OGG1;1909
|
CUX1;22551
|
p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849
|
c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988
| 0no label
|
A single @GENE$ mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.
| 5,868,303
|
SQSTM1;31202
|
TIA1;20692
|
c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407
|
p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866
| 0no label
|
(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.
| 4,998,745
|
GJB6;4936
|
MITF;4892
|
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
|
Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, @VARIANT$), LAMA2 @VARIANT$ (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). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization.
| 8,739,608
|
SCN5A;22738
|
KCNH2;201
|
c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;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
|
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; @VARIANT$ of TACR3).
| 3,888,818
|
KAL1;55445
|
NELF;10648
|
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
|
Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.
| 4,293,318
|
DCTN1;3011
|
VAPB;36163
|
p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583
|
p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276
| 0no label
|
@GENE$Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in @GENE$ (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.
| 8,152,424
|
CCDC88;49992
|
DCC netrin 1 receptor;21081
|
p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919
|
c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260
| 0no label
|
Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).
| 5,953,556
|
TEK;397
|
CYP1B1;68035
|
p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183
|
p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918
| 0no label
|
Missense variants in the @GENE$ gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients.
| 6,707,335
|
NEFH;40755
|
GRN;1577
|
P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372
|
R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852
| 0no label
|
Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts. Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in @GENE$, rs143224912 in SETDB1 and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified. The ISG20L2 and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.
| 6,637,284
|
S100A13;7523
|
ISG20L2;12814
|
rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706
|
p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284
| 0no label
|
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 @VARIANT$ with @GENE$ p.I2547T and SETX p.T14I).
| 4,293,318
|
VAPB;36163
|
SETX;41003
|
p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953
|
p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127
| 0no label
|
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
| 7,877,624
|
PAX3;22494
|
TYRO3;4585
|
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
|
p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Sanger sequencing Sanger sequencing was performed on available samples for confirmation of GFI1 and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.
| 7,026,993
|
MYO6;56417
|
GFI1;3854
|
p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872
|
c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203
| 0no label
|
Mutations of @GENE$ and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing. Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).
| 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
|
Four genes (including @GENE$, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.
| 5,725,008
|
AGXT2;12887
|
SCAP;8160
|
p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937
|
p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902
| 0no label
|
This mutation changes codon 554 from arginine to a stop codon (c.1160C>T; @VARIANT$) and has been previously reported. The mother did not carry this luteinizing hormone/choriogonadotropin receptor (@GENE$) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the @GENE$, SRY, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant @VARIANT$ lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant.
| 5,893,726
|
LHCGR;37276
|
AMH;68060
|
p.Arg554Stop;tmVar:p|SUB|R|554|X;HGVS:p.R554X;VariantGroup:1;CorrespondingGene:3973;RS#:368991748
|
Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626
| 0no label
|
Gln91Arg, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant @VARIANT$ of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as @GENE$ through a digenic/oligogenic model to contribute to IHH. Case P06 had a missense variant in GADL1 (p. Ser221Cys), predicted as probably damaging. GADL1 expression is present during early brain development and is higher in olfactory bulb than that in other tissues, where is an active area for regeneration and migration of GnRH neurons. Consistent with this observation, case P06 was affected by anosmia, indicating that the function of GADL1 might be involved in the etiology of IHH (Table 2). A de novo @GENE$ frameshift deletion (p. Gly52Asnfs*14) resulting in truncation of the protein was detected in case P09.
| 8,152,424
|
CCDC88C;18903
|
SPRED3;28061
|
c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260
|
p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125
| 0no label
|
(A) Patient with homozygous variants in both @GENE$ and SGCA genes. NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and @VARIANT$ (R284C) in ANO5 and @GENE$ genes, respectively.
| 6,292,381
|
ANO5;100071
|
SGCA;9
|
c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516
|
c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431
| 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 @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation 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
|
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 @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 G4290R) in the @GENE$ gene.
| 6,707,335
|
MATR3;7830
|
DYNC1H1;1053
|
G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568
|
P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187
| 0no label
|
We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.
| 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
|
p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918
| 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 ALS2 may be causative for adult-onset sALS. @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.
| 6,707,335
|
MATR3;7830
|
DYNC1H1;1053
|
G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568
|
P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187
| 0no label
|
Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that 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
|
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
|
Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.
| 5,966,321
|
DVL3;20928
|
SCRIB;44228
|
p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256
|
p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676
| 0no label
|
After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in @GENE$, @VARIANT$ in @GENE$ and rs138355706 in S100A3, and one novel variant in S100A13, were identified.
| 6,637,284
|
ISG20L2;12814
|
SETDB1;32157
|
rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737
|
rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912
| 0no label
|
The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and @GENE$ @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.
| 5,966,321
|
PTK7;43672
|
SCRIB;44228
|
c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292
|
c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763
| 11
|
In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.
| 6,161,649
|
ENG;92
|
MAP4K4;7442
|
c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566
|
c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022
| 0no label
|
Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.
| 6,081,235
|
TRPV4;11003
|
CAPN11;21392
|
p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342
|
c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137
| 0no label
|
Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).
| 2,737,700
|
GJB2;2975
|
GJB3;7338
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
|
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
| 0no label
|
Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, @VARIANT$) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that Q1916 is highly conserved across mammals (red font). (C) Topology model of the alpha-subunit of LTCC. The localization of the mutation is indicated by a red dot, and polymorphisms are indicated by green dots. (D) A variant (@VARIANT$, p.R1193Q) in SCN5A.
| 5,426,766
|
CACNA1C;55484
|
SCN5A;22738
|
p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963
|
c.3578G>A;tmVar:c|SUB|G|3578|A;HGVS:c.3578G>A;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287
| 11
|
The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).
| 3,842,385
|
EDA;1896
|
WNT10A;22525
|
p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896
|
c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326
| 0no label
|
Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, @VARIANT$ (c.379C>T) and a heterozygous frameshift mutation in exon 4 of HNF1A, P291fsinsC (@VARIANT$). @GENE$ therapy was completely discontinued and she was started on glipizide (1.25 mg once daily) with the dose titrated to 2.5 mg once daily based on blood sugar checks, with weekly blood sugar reviews and close support from a diabetes specialist nurse practitioner.
| 4,090,307
|
HNF4A;395
|
Insulin;173
|
R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226
|
c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825
| 0no label
|
Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
SNAI3;8500
|
TYRO3;4585
|
p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
|
c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 11
|
(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of NOD2 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 @VARIANT$ substitution with a score of 0.999.
| 3,975,370
|
IL10RA;1196
|
NOD2;11156
|
R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561
|
K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561
| 0no label
|
The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father. Sequence analyses of @GENE$ and WNT10A genes.
| 3,842,385
|
WNT10A;22525
|
EDA;1896
|
G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329
|
Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955
| 0no label
|
In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in @GENE$ and a de novo variant, @VARIANT$ in @GENE$. DFNB1 as a molecular etiology was excluded from this subject, while digenic inheritance of SNHL can be proposed for this subject because the pathogenic potential of p.R341C was strongly supported by significant conservation of the p.R341 residue among various species and by the absence of this variant among the 666 control chromosomes from normal hearing control subjects.
| 4,998,745
|
GJB2;2975
|
MITF;4892
|
c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943
|
p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251
| 11
|
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).
| 3,888,818
|
NELF;10648
|
TACR3;824
|
p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730
|
p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871
| 0no label
|
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.
| 7,877,624
|
SOX10;5055
|
SNAI2;31127
|
c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286
|
c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Since the FGFR1 @VARIANT$ 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 (@GENE$ @VARIANT$).
| 8,152,424
|
DCC;21081
|
CCDC88C;18903
|
c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260
|
p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192
| 0no label
|
Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, @GENE$ p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.
| 5,966,321
|
CELSR1;7665
|
DVL3;20928
|
p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026
|
p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292
| 0no label
|
To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).
| 2,737,700
|
GJB3;7338
|
GJB2;2975
|
A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
| 0no label
|
The WT structure of @GENE$ is shown in purple, and the mutant structure of FLNB is shown in green. The side chains of R/@VARIANT$ and A/T2282 are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C).
| 7,279,190
|
FLNB;37480
|
TTC26;11786
|
L566;tmVar:p|Allele|L|566;VariantGroup:1;CorrespondingGene:2317;RS#:778577280
|
p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260
| 0no label
|
In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.
| 6,707,335
|
SPG11;41614
|
UBQLN2;81830
|
A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493
|
M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941
| 0no label
|
Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.
| 6,081,235
|
TOR2A;25260
|
HS1BP3;10980
|
p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211
|
p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342
| 0no label
|
Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ 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
|
FZD6;2617
|
FZD1;20750
|
c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865
|
c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970
| 0no label
|
Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.
| 6,081,235
|
VPS13C;41188
|
UNC13B;31376
|
p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342
|
c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137
| 0no label
|
Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: @VARIANT$, 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 DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.
| 6,081,235
|
HS1BP3;10980
|
UNC13B;31376
|
p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615
|
c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011
| 0no label
|
Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).
| 2,737,700
|
GJB2;2975
|
GJB3;7338
|
299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706
|
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
| 0no label
|
Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by @GENE$/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated @GENE$. Immunocomplex of myc-pendrin @VARIANT$, S166N and @VARIANT$ was not affected.
| 7,067,772
|
EphA2;20929
|
pendrin;20132
|
L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985
|
F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409
| 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$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).
| 2,737,700
|
Cx26;2975
|
Cx31;7338
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
|
A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
| 0no label
|
Notably, the common variants @GENE$-p.K897T and @GENE$-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.
| 5,578,023
|
KCNH2;201
|
KCNE1;3753
|
C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757
|
p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330
| 0no label
|
In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2). Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.
| 6,161,649
|
PTPN13;7909
|
MAP4K4;7442
|
c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588
|
p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588
| 0no label
|
The @VARIANT$ and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel 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
|
R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049
| 0no label
|
There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.
| 6,565,573
|
COL4A5;133559
|
COL4A3;68033
|
c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287
|
c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174
| 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 @VARIANT$ (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo. In patient AVM206, the de novo heterozygous missense variant c.2075A>G (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, @GENE$ mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).
| 6,161,649
|
SCUBE2;36383
|
N-cadherin;20424
|
p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588
|
c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588
| 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 @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ 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
| 11
|
In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).
| 2,737,700
|
GJB6;4936
|
GJB2;2975
|
235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943
|
N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311
| 0no label
|
The presence of concomitant mutations, such as the @GENE$ T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.
| 5,671,988
|
TCF3;2408
|
TNFRSF13B;49320
|
T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929
|
C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387
| 0no label
|
In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain. Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.
| 6,707,335
|
SPG11;41614
|
ubiquilin-2;81830
|
A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493
|
E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795
| 0no label
|
The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) . In vitro evaluation of a similarly truncated @GENE$ isoenzyme comprising amino acids 1 to 593 alone abolished H2O2-generating activity. Moreover, similar truncations in the highly homologous @GENE$ [p.Q686*, p.R701*, p.(G418fsX482);(IVS19-2A>C), @VARIANT$] are associated with CH or severely impaired H2O2-generating activity in vitro.
| 5,587,079
|
DUOX1;68136
|
DUOX2;9689
|
c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905
|
p.S965fsX994;tmVar:p|FS|S|965||994;HGVS:p.S965fsX994;VariantGroup:16;CorrespondingGene:50506
| 0no label
|
A novel variant SCRIB c.1853A > G (@VARIANT$) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 @VARIANT$ and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).
| 5,966,321
|
CELSR1;7665
|
SCRIB;44228
|
p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676
|
p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078
| 0no label
|
Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.
| 7,877,624
|
PAX3;22494
|
MITF;4892
|
c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366
|
p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886
| 0no label
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.