Identification of known and novel genetic variants in sensorineural hearing loss: insights from whole exome sequencing in Indian families

Background: Hearing loss (HL) is one of the most common congenital anomalies and is a complex etiologically diverse condition. Molecular genetic characterization of HL remains challenging owing to the high genetic heterogeneity. This study aimed to screen for potential disease-causing genetic variations in a cohort of Indian patients with congenital bilateral severe-to-profound sensorineural HL. Methods and results: The study cohort consisted of 105 individuals, including 31 patients from 25 families with congenital HL classified as severe to profound bilateral. The patients were identified based on clinical evaluation and family history. Whole exome sequencing (WES) was performed to detect the genetic variations within these families. Variant co-segregation was examined using Sanger sequencing, and amino acid conservation was assessed using Clustal Omega. The 3D protein structure prediction was performed for the novel missense variants. WES 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.811 A > T, COL4A6 c.227G > A, and CLIC5 c.401 A > G). Co-segregation 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 HL. These findings enhance our understanding of the genetic landscape of HL and could have implications for the diagnosis and genetic counselling of affected families. Keywords: CDH23; CLIC5; COL4A6; Indian families; Novel variants; SLC26A4; Sensorineural hearing loss; Whole exome sequencing.