Identification of Known and Novel Genetic Variants in Sensorineural Hearing Loss: Insights from Whole Exome Sequencing in Indian Families

Background Hearing loss is one of the most common congenital anomalies and is a complex etiologically diverse condition. Molecular genetic characterization of hearing loss remains challenging owing to the high genetic heterogeneity. This study aimed to screen for potential disease-causing genetic variations in a specific cohort of Indian patients with congenital bilateral severe-to-profound sensorineural hearing loss. Methods and results The study cohort consisted of 105 individuals, including 31 patients from 25 families with congenital hearing loss classified as severe to profound bilateral. The patients were identified based on clinical evaluation and family history. Whole exome sequencing was performed to detect the genetic variations within these families. Variant cosegregation was examined using Sanger sequencing, and amino acid conservation was assessed using Clustal Omega. Whole exome sequencing and subsequent data analysis identified five novel variants and five previously reported pathogenic variants. The novel variants included a homozygous 23 bp frameshift deletion ( CDH23 c.6571_6593del), compound heterozygous stop-gain variant ( SLC26A4 c.1416G > A), and three homozygous missense variants ( CDH23 c.811A > T, COL4A6 c.227G > A, and CLIC5 c.401A > G). Cosegregation was confirmed within families. Frameshift deletion and stop-gain variants were classified as pathogenic, while missense variants were categorized as variant of uncertain significance. Pathogenicity prediction tools and amino acid conservation analyses further supported the pathogenic potential of the novel variants. Conclusions The identification of novel and previously reported variants in familial cases underscores the importance of WES in genetic analysis of hearing loss. These findings enhance our understanding of the genetic landscape of hearing loss and may have implications for the diagnosis and genetic counselling of affected families.