Genetic Spectrum of Autosomal Recessive Non-Syndromic Hearing Loss in Pakistani Families

<div><p>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 <i>GJB2</i> while mutations in <i>MYO15A</i> account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in <i>GJB2</i> and <i>MYO15A</i>. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP) genotyping in the families that did not carry mutations in <i>GJB2</i> or <i>MYO15A</i>. 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 (<i>GJB2</i> (c.598G>A, p.Gly200Arg); <i>MYO15A</i> (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser), <i>TMC1</i> (c.362+18A>G), <i>BSND</i> (c.97G>C, p.Val33Leu), <i>TMPRSS3</i> (c.726C>G, p.Cys242Trp) and <i>MSRB3</i> (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. <i>GJB2</i> accounted for 53% of the families, while mutations in <i>MYO15A</i> 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.</p>