Genetic Diagnosis of Non-Syndromic Hearing Loss in South Indian Consanguineous Families Using Whole-Exome Sequencing.

Background and

Objectives

Hereditary hearing loss is the most common auditory disability among various disabilities. Consanguineous populations have been found to have autosomal recessive disorders twice as often as in the general population. This study aimed to highlight the phenotypic and genetic complexity of non-syndromic hearing loss (NSHL) in South Indian consanguineous families. Materials and

Methods

Whole-exome sequencing (WES) was performed on individuals with NSHL who were negative for common deafness-causing genes (GJB2, GJB6, SLC26A4, and MTRNR1). The candidate variants identified were correlated with ROH regions identified using the Automap tool. Sanger sequencing was performed for validation, followed by segregation analysis for the available family members. The effects of the candidate variants were analyzed using an in silico structural approach and the ACMG guidelines.

Results

WES identified variants, including a stop-gain, an indel, and a missense mutation, in the genes SIX1, MYO7A, MYO3A, and MYO15A. Three variants were classified as likely pathogenic, one variant as a variant of uncertain significance (VUS), and one variant as likely benign. Homozygous variants in MYO15A and MYO7A were identified within ROH regions, indicating autosomal recessive inheritance. Additionally, two heterozygous variants in the SIX1 and MYO3A genes were identified. This study indicates a high degree of genotypic and phenotypic heterogeneity of hearing loss among affected individuals.

Conclusions

This integrated approach, which combines homozygosity mapping with WES, could be effective for diagnosing NSHL in affected individuals. Further genetic screening and characterization of NSHL in consanguineous families is also warranted. Genetic testing in high-risk populations could be a valuable method for diagnosing genetic hearing loss in children.