Dataset Information

Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss.

ABSTRACT: To investigate the causative genetic mutations in 12 Pakistani families with nonsyndromic or syndromic hearing loss.Mutations in the most common causative gene for hearing loss, GJB2, were evaluated by Sanger sequencing. Targeted next-generation sequencing or whole-exome sequencing was used to analyze the genomic DNA samples from 11 probands with hearing loss. Sanger sequencing was performed to verify all identified variants.We found pathogenic, or likely to be pathogenic, mutations in all 12 families, including six known mutations in GJB2, SLC26A4, LHFPL5, and USH2A and eight novel mutations in ESPN, MYO7A, LRTOMT, PCDH15, USH2A, or EPS8L2. Notably, four compound heterozygous mutations in the MYO7A and USH2A genes were detected in two consanguineous families. In addition, the novel frameshift mutation in EPS8L2 was first documented in Pakistan.Our study increases the spectrum of mutations associated with hearing loss in the Pakistani population. In addition, our study highlights the fact that compound heterozygous mutations, although rare, can occur in consanguineous families.

SUBMITTER: Wang R

PROVIDER: S-EPMC5444417 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss.

Wang Rongrong R Han Shirui S Khan Amjad A Zhang Xue X

Genetic testing and molecular biomarkers 20170310 5

<h4>Aim</h4>To investigate the causative genetic mutations in 12 Pakistani families with nonsyndromic or syndromic hearing loss.<h4>Methods</h4>Mutations in the most common causative gene for hearing loss, GJB2, were evaluated by Sanger sequencing. Targeted next-generation sequencing or whole-exome sequencing was used to analyze the genomic DNA samples from 11 probands with hearing loss. Sanger sequencing was performed to verify all identified variants.<h4>Results</h4>We found pathogenic, or lik ...[more]

PMID: 28281779

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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

Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss.

Publications

Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss.

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