Targeted Next-Generation Sequencing Analysis Reveals a Novel Genetic Variant in Gene in an Indian Family with Postlingual Nonsyndromic Hearing Loss.

Hereditary nonsyndromic hearing loss (NSHL) is an extremely heterogeneous disorder, both genetically and clinically. Myosin VI () pathogenic variations have been reported to cause both prelingual and postlingual forms of NSHL. Postlingual autosomal dominant cases are often overlooked for genetic etiology in clinical setups. In this study, we used next-generation sequencing (NGS)-based targeted deafness gene panel assay to identify the cause of postlingual hearing loss in an Indian family. The proband and his father from a multigenerational Indian family affected by postlingual hearing loss were examined via targeted capture of 129 deafness genes, after excluding gap junction protein beta 2 () pathogenic variants by Sanger sequencing. NGS data analysis and co-segregation of the candidate variants in the family were carried out. The variant effect was predicted by tools and interpreted following American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. A novel heterozygous transversion c.3225T>G, p.(Tyr1075*) in gene was identified as the disease-causing variant in this family. This stop-gained variant is predicted to form a truncated myosin VI protein, which is devoid of crucial cargo-binding domain. PCR-RFLP screening in 200 NSHL cases and 200 normal-hearing controls showed the absence of this variant indicating its nature in the population. Furthermore, we reviewed variants reported from various populations to date. To the best of our knowledge, this is the first family with -associated hearing loss from an Indian population. The study also highlights the importance of deafness gene panels in molecular diagnosis of -negative pedigrees, contributing to genetic counseling in the affected families.