Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families

Abstract

Hearing loss is a genetically heterogeneous disorder affecting approximately 360 million people worldwide and is among the most common sensorineural disorders. Here, we report a genetic analysis of seven large consanguineous families segregating prelingual sensorineural hearing loss. Whole-exome sequencing (WES) revealed seven different pathogenic variants segregating with hearing loss in these families, three novel variants (c.1204G>A, c.322G>T, and c.5587C>T) in <i>TMPRSS3, ESRRB,</i> and <i>OTOF</i>, and four previously reported variants (c.208C>T, c.6371G>A, c.226G>A, and c.494C>T) in <i>LRTOMT</i>, <i>MYO15A</i>, <i>KCNE1</i>, and <i>LHFPL5</i>, respectively<i>.</i> All identified variants had very low frequencies in the control databases and were predicted to have pathogenic effects on the encoded proteins. In addition to being familial, we also found intersibship locus heterogeneity in the evaluated families. The known pathogenic c.226C>T variant identified in <i>KCNE1</i> only segregates with the hearing loss phenotype in a subset of affected members of the family GCNF21. This study further highlights the challenges of identifying disease-causing variants for highly heterogeneous disorders and reports the identification of three novel and four previously reported variants in seven known deafness genes.