Identification of Distinct Genetic Variants from a Whole-exome Sequencing of Syndromic Anorectal Malformation Specific to North Indian Registry

Anorectal Malformations (ARM) are congenital anomalies affecting the anus and rectum, with a global incidence of 1 in 5000 live births. Despite clinical advancements, the genetic basis of ARM remains largely unknown. Our study utilized whole-exome sequencing (WES) on ARM-diagnosed individuals to identify rare and potentially pathogenic variants. We prioritized 23 variants using CONVEX and AION pipelines, followed by Sanger sequencing validation. Cross-referencing with existing GWAS datasets identified two common variants, ISL1 and EFNA1, both reported in European ancestry, suggesting a genetic architecture. Network analysis using Cytoscape and Cytohubba highlighted PKD1, PKD2, and PKHD1 as important hub genes and pathways for ARM, including several developmental pathways. Furthermore, our structural variant analysis identified a prioritized variant within a copy number variant. Our findings provide novel insights into syndromic ARM, which may lead to improved genetic diagnosis and personalized interventions.