Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

Abstract

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

Report of rare and novel mutations in candidate genes in a cohort of hearing‐impaired patients

“…The majority of MYO15A variants have been related to congenital or postlingual deafness (Zhang et al, 2019). They are frequently found in consanguineous families in Mideast countries (Doll et al, 2020;Noman et al, 2019;…”

“…The majority of MYO15A variants have been related to congenital or postlingual deafness (Zhang et al, 2019). They are frequently found in consanguineous families in Mideast countries (Doll et al, 2020; Noman et al, 2019; Shafique et al, 2014). In contrary, genetic impact of MYO15A was less reported in China (Wang et al, 2020; Zhang et al, 2019), where nonconsanguineous marriage is predominant.…”

“…A large proportion of hearing‐impaired patients carry mutations in rare or novel genes undetected in regular genetic screening (Chen et al, 2014; Doll et al, 2020; Yang et al, 2013). Routine Sanger sequencing failed to address this issue due to the enormous DNA sequences in numerous genes.…”

Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice

“…Genetic testing for etiologic evaluation has become a standard of care in people with congenital or childhood-onset sensorineural HL, which is caused by pathologies of the inner ear and auditory nerve ( 4 , 5 ). Recent studies have shown that screening all recognized HL genes for variants reveals underlying cause in about half of the affected individuals, leaving a significant portion of people with HL with an unknown etiology ( 6 – 9 ). In the era of emerging genetic therapies for HL, finding the etiology of HL in affected individuals has become a critical task.…”

Genetics of Hearing Impairment

“…In both studies, GJB2 and STRC were the most frequently mutated genes among the recessive cases, and MYO6 among the dominant ones. Finally, in the third broad epidemiological study in this Special Issue, Doll et al investigated 21 Pakistani consanguineous families with autosomal recessive HI [16]. The cohort included 5 syndromic and 16 non-syndromic cases.…”