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

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.

The Genetic Basis of Nonsyndromic Hearing Loss in Indian and Pakistani Populations

“…A total of six different mutations were identified in the study, with W24X as the major mutation found, followed surprisingly by c.35delG being the second most prevalent, surpassing Q124X, W77X, V153I, and T8M. Furthermore, sequence analysis of GJB2 in 30 consanguineous families with NSHL from different regions of Punjab, by Shafique et al (2014), revealed the presence of mutations in this gene in 16 families (53%). W24X and W77X were the most common mutations found.…”

“…These seventeen missense, nonsense, and splice site mutations are located in exons encoding motor and first FERM domains of MYO15A. In a more recent study, 4/30 (13%) families were found to have mutation in MYO15A (Shafique et al, 2014). These include four unreported variants, of which two were splice site mutations (c.9948G > A and c.3866 + 1G > A), one was a nonsense (p.R2923X), and one missense mutation (p. F2741S).…”

“…We previously estimated that TMC1 mutations account for approximately 5% of recessive deafness in a mixed cohort of 230 Pakistani and Indian families (6/10 Punjabi families) (Kurima et al, 2002). Of the 30 families analyzed by Shafique et al (2014), 3 (10%) were found to carry TMC1 mutations.…”

Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells

“…Homozygosity mapping was subsequently performed in families W06-0987, W09-1575 and W09-1600 as part of a larger project directed toward the identification of genetic defects underlying sensorineural HI in consanguineous Pakistani families and nonconsanguineous families of The Netherlands. 27,30 In the only affected individual II.3 of family W06-0987, homozygosity mapping revealed nine homozygous regions larger than 1 Mb (Table 1). The second large homozygous region harbored TRIOBP, the gene associated with the known arNSHI type DFNB28.…”

Mutations of GJB2 encoding connexin 26 contribute to non-syndromic moderate and severe hearing loss in Pakistan

“…Mutations in GJB2 account for 6.9% (95%confidence interval, 3.2–10.4%), of moderate to profound deafness in Pakistanis living in the UK, as inferred from analyses of samples from 123 sib pairs [8]. However, the contribution of GJB2 mutations to deafness in Pakistan was reported to be as high as 53%, (95% confidence interval, 35–71%), in a study involving 30 families with severe to profound deafness [9]. The large discrepancy between the results of this research on 30 families and the estimates of frequency of mutations in GJB2 obtained from previous studies is not clear, although small sample size of these studies may have contributed to the difference.…”