A whole-exome analysis of non-syndromic hearing loss patients from India reveals a wide spectrum of known and novel mutations

Abstract

Abstract Background Non-syndromic hearing loss (NSHL) is characterized by congenital mild-to-profound sensorineural hearing impairment. It affects 1 in 1000 neonates in India. While we have a large genetically deaf population in India, our knowledge about the specific causes behind the disorder is almost non-existent. We carried out clinical audiological characterization in a cohort of 43 NSHL patients from India and subsequently performed whole exome seqencing (WES) to create a high-resolution genomic architecture behind congenital hearing loss. Furthermore, molecular dynamics simulations (MDS) and in silico homology modeling were conducted for some novel and missense variants. Moreover, we investigated the genotype-phenotype relationship to reach a final diagnosis for NSHL. Results A total of 28 rare and deleterious mutations were identified in 21 genes previously reported based on the hereditary hearing loss database. We could accurately diagnose 51% of the patients (n = 22/43) in our NSHL cohort. The presence of pathogenic and likely pathogenic mutations was confirmed by Sanger sequencing. Additionally, in silico homology modelling and MDS of mutations in GJB2, SLC26A4, GPSM2, TMPRSS3, CIB2, and TSPEAR revealed that the stability of the mutant proteins was altered compared to their wild-type, suggesting their potential pathogenic role. Conclusion The WES findings would help create a strong knowledge base for deafness genetics in the Indian population, which will aid in high-quality genetic care for families with this disability that was challenging using traditional diagnostic methods. The therapeutic use of this WES finding will help guide clinical care and genetic counseling for individuals with NSHL.