Genetic Insights into Chronic Kidney Disease through Whole Exome Sequencing of South Indian Patients: A Pilot study

ABSTRACT

Nephrotic syndrome (NS) contributes significantly to chronic kidney disease (CKD) mortality worldwide. Whole-exome sequencing (WES) was used to identify pathogenic and regulatory variants associated with NS in a Tamil Nadu patient cohort, with the long-term goal of developing a region-specific diagnostic strategy. The genomic DNA was extracted from 15 patients with proteinuria and 7 healthy controls and subjected to WES. Variants were systematically filtered against human reference genome (GRCh38/hg38) and prioritized them using multiple prediction algorithms, including CADD, SIFT, FATHMM, PredictSNP2, and ClinVar annotations. Protein stability effects were evaluated using MUPro and PremPS tools and assessed functional consequences through PANTHER cSNP analysis. Variant distribution patterns and pathogenicity scores were visualized using scatter plots and genotype heat maps. A total of 266 variants were identified across 59 nuclear genes previously reported to be associated with NS, including 114 non-synonymous substitutions. Integrated computational filtering prioritized 14 variants predicted to have deleterious effects. Functional annotation highlighted three variants of particular significance: CUBN (rs139724058), FAT1 (rs3733415), and TRPC6 (rs36111323). In this pilot study, we identified candidate genetic variants that may contribute to NS susceptibility in South Indian populations, strongly suggesting the presence of population-specific genetic risk factors. These findings provide preliminary evidence to support the development of a region specific diagnostic gene panel. However, validation in larger cohorts and functional studies will be essential to establish clinical utility and address precision medicine strategies.