Caste-based genetic diagnosis: evidence from a pathogenic <i>SLC26A4</i> variant implicated in hereditary hearing loss

Variants in the SLC26A4 gene are the most common cause of hereditary hearing loss in Pakistan, and the second most common cause worldwide. Advances in genetic diagnosis can make it more time-efficient, cost-effective, and accessible to clinicians and patients. The study aimed to screen 260 consanguineous Pakistani families with hereditary hearing loss for the DFNB4/PDS locus and to detect pathogenic SLC26A4 variants across different castes. We used homozygosity mapping to predict pathogenic variants and selected seven SLC26A4 exons for direct sequencing in 19 of the 23 DFNB4/PDS-linked families, based on haplotype comparison. Sequencing data were analyzed using Chromas software (Technelysium Pty. Ltd, version 1.45), and the detected variants were stratified by castes of the enrolled families. Four missense variations (c.269C>T, c.716T>A, c.1337A>G, and c.1667A>G) were identified in 16 families, as predicted by haplotype analysis, in exons 3, 6, 11, and 15 of SLC26A4. The Q446R (c.1337A>G) variant was identified in eight families, all belonging to the Arain caste of Pakistan. Caste data from a previous study of Pakistani patients similarly supported its potential role in caste-based genetic diagnosis. In PKDF497, six double heterozygotes for variants of GJB2 and SLC26A4 were detected without hearing loss. We present evidence supporting caste-based targeted variant screening for hereditary hearing loss. Following additional validation studies, caste-based targeted variant screening for common hereditary disorders could be implemented in developing countries, particularly in South Asia, to provide faster and more cost-effective molecular diagnosis compared to whole-genome or whole-exome sequencing.