Dataset Information

Proband Whole-Exome Sequencing Identified Genes Responsible for Autosomal Recessive Non-Syndromic Hearing Loss in 33 Chinese Nuclear Families.

ABSTRACT: Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous disease involving more than 70 pathogenic genes. However, most ARNSHL families have small-sized pedigrees with limited genetic information, rendering challenges for the molecular diagnosis of these patients. Therefore, we attempted to establish a strategy for identifying deleterious variants associated with ARNSHL by applying proband whole-exome sequencing (proband-WES). Aside from desiring to improve molecular diagnostic rates, we also aimed to search for novel deafness genes shared by patients with similar phenotype, making up for the deficiency of small ARNSHL families. In this study, 48.5% (16/33) families were detected the pathogenic variants in eight known deafness genes, including 10 novel variants identified in TMPRSS3 (MIM 605551), MYO15A (MIM 602666), TMC1 (MIM 606706), ADGRV1 (MIM 602851), and PTPRQ (MIM 603317). Apart from six novel variants with a truncating effect (nonsense, deletion, insertion, and splice-site), four novel missense variants were not found in 200 unrelated control population by using Sanger sequencing. It is important to note that none of novel genes were shared across different pedigrees, indicating that a larger sample size might be needed. Proband-WES is a cost-effective and precise way of identifying causative variants in nuclear families with ARNSHL. This economical strategy may be appropriated as a clinical application to provide molecular diagnostics, genetic counseling, and individualized health maintenance measures for patients with ARNSHL at hearing clinics.

SUBMITTER: Sang S

PROVIDER: S-EPMC6650584 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Proband Whole-Exome Sequencing Identified Genes Responsible for Autosomal Recessive Non-Syndromic Hearing Loss in 33 Chinese Nuclear Families.

Sang Shushan S Ling Jie J Liu Xuezhong X Mei Lingyun L Cai Xinzhang X Li Taoxi T Li Wu W Li Meng M Wen Jie J Liu Xianlin X Liu Jing J Liu Yalan Y Chen Hongsheng H He Chufeng C Feng Yong Y

Frontiers in genetics 20190717

Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous disease involving more than 70 pathogenic genes. However, most ARNSHL families have small-sized pedigrees with limited genetic information, rendering challenges for the molecular diagnosis of these patients. Therefore, we attempted to establish a strategy for identifying deleterious variants associated with ARNSHL by applying proband whole-exome sequencing (proband-WES). Aside from desiring to improve molecular dia ...[more]

PMID: 31379920

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Project description:The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL) in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP) genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg); MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser), TMC1 (c.362+18A>G), BSND (c.97G>C, p.Val33Leu), TMPRSS3 (c.726C>G, p.Cys242Trp) and MSRB3 (c.20T>G, p.Leu7Arg)). Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48%) missense changes, 4 (19%) nonsense mutations, 3 (14%) intronic mutations, 2 (9%) splice site mutations and 2 (9%) frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13%) cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations.

Dataset Information

Proband Whole-Exome Sequencing Identified Genes Responsible for Autosomal Recessive Non-Syndromic Hearing Loss in 33 Chinese Nuclear Families.

Publications

Proband Whole-Exome Sequencing Identified Genes Responsible for Autosomal Recessive Non-Syndromic Hearing Loss in 33 Chinese Nuclear Families.

Similar Datasets

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