Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families.

Sobia Shafique,Saima Siddiqi,Maleeha Azam,Margit Schraders,Kehkashan Mazhar,Atika Mansoor,Alamdar Hussain,Celia Zazo Seco,Muhammad Ajmal,Jaap Oostrik,Hannie Kremer,Ammad Bilal,Tim M Strom,Raheel Qamar,Syed Tahir A Shah,Humaira Ayub

doi:10.1371/journal.pone.0100146

Abstract

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.

Highlights

Deafness or hearing loss is the most common congenital sensorineural disorder affecting about 1 in 1000 children
In addition to the 6 recurrent GJB2 mutations, a novel homozygous change c.598G.A (p.Gly200Arg) was found in one consanguineous family DFR10 (Table 2); as predicted by the Have your Protein Explained (HOPE) server the larger side chain of the mutant residue arginine might well affect the proper folding of the cysteine rich domain
In a cohort of 30 autosomal recessive non-syndromic hearing loss (ARNSHL) families the genetic defects were identified in 9 known deafness genes; GJB2, MYO15A, TMC1, BSND, TMPRSS3, MSRB3, HGF, SLC26A4 and TMIE

Summary

Introduction

Deafness or hearing loss is the most common congenital sensorineural disorder affecting about 1 in 1000 children. Genetic factors contribute to approximately half of the cases of hearing loss [1], which can be either syndromic or non-syndromic. The former is responsible for about 30% of prelingual deafness in combination with abnormalities of other organs. Non-syndromic deafness is usually due to abnormalities of the middle and/or the inner ear and is found in 70% of the hereditary cases [2]. The disease is genetically heterogeneous and currently 134 loci have been determined and 80 genes identified for the non-syndromic type (Hereditary Hearing Loss Homepage, URL: http:// hereditaryhearingloss.org/). More than 400 syndromes are known with deafness as one of the symptoms and for many of these the causative genes have been identified (Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/omim)

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