Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan

Abstract

Hearing loss affects 380 million people worldwide due to environmental or genetic causes. Determining the cause of deafness in individuals without previous family history of hearing loss is challenging and has been relatively unexplored in Pakistan. We investigated the spectrum of genetic variants in hearing loss in a cohort of singleton affected individuals born to consanguineous parents. Twenty-one individuals with moderate to severe hearing loss were recruited. We performed whole-exome sequencing on DNA samples from the participants, which identified seventeen variants in ten known deafness genes and one novel candidate gene. All identified variants were homozygous except for two. Eleven of the variants were novel, including one multi-exonic homozygous deletion in OTOA. A missense variant in ESRRB was implicated for recessively inherited moderate to severe hearing loss. Two individuals were heterozygous for variants in MYO7A and CHD7, respectively, consistent with de novo variants or dominant inheritance with incomplete penetrance as the reason for their hearing loss. Our results indicate that similar to familial cases of deafness, variants in a large number of genes are responsible for moderate to severe hearing loss in sporadic individuals born to consanguineous couples.

Figure 1

Audiograms for selected participants and partial protein sequence alignments from diverse vertebrate species. (A) Audiometry was performed under ambient noise conditions and hearing threshold is classified as moderate to severe or severe. (B) Clustal alignments show conservation of amino acids affected by novel missense variants. The residues are indicated in bold. All amino acids affected by variants are conserved except for one in BSND and BHLHE22. ‘o’ right ear, ‘x’ left ear.