Exome Sequencing Identifies Novel Variants Causing Hearing Loss in Three Consanguineous Pakistani Families: Insights From Genomics and Bioinformatics Analyses.

BACKGROUND: Hearing impairment is a genetically heterogeneous disorder and represents a significant health concern, particularly in consanguineous populations where autosomal recessive forms are more prevalent. Pakistani families provide an important population for investigating the genetic basis of hereditary hearing impairment. OBJECTIVE: The current study was aimed to elucidate the genetic basis of hearing impairment in consanguineous Pakistani families. MATERIAL AND METHODS: Three consanguineous Pakistani families comprising 11 affected individuals presenting bilateral profound hearing loss were investigated using Exome Sequencing (ES). Sanger sequencing was used for segregation analysis of candidate variant(s) in each pedigree. Structural modeling of both wild-type and mutant proteins were performed using bioinformatic tools to assess the functional impact of candidate variants. RESULTS: ES data analysis revealed homozygous missense variants in MSRB3 (c.244T>G; p.Cys82Gly), ESRP1 (c.353T>C; p.Leu118Pro) and TMC1 (c.1749C>G; p.Asn583Lys) in family 1, 2, and 3 respectively. These variants are predicted to be "deleterious" by multiple bioinformatic tools, affecting highly conserved residues of candidate protein, and are absent in homozygous form in public databases. Sanger sequencing validated the co-segregation of the candidate variants within their respective families. Structural modeling of the wild-type and mutant proteins predicted that the candidate variants lead to structural alterations that strengthens the evidence supporting their pathogenicity. CONCLUSION: This study expands the mutational spectrum of MSRB3, ESRP1 and TMC1 genes associated with hearing loss. Furthermore, carrier screening and genetic counselling can be developed for affected families based on the findings obtained from the current study. The data obtained may also enhance our understanding of the pathophysiology of hearing loss ultimately guiding us in the development of potential therapeutics.