Distinct genetic variants from the whole-exome sequencing of syndromic anorectal malformations: A cross-sectional...

Anorectal malformations (ARMs) are congenital anomalies affecting the anus and rectum, with a global incidence of 1 in 5,000 live births. Despite clinical advancements, the genetic basis of ARMs remains largely unknown. Our study utilized whole-exome sequencing (WES) on ARM-diagnosed individuals to identify rare and potentially pathogenic variants. We prioritized 20 variants by using consensus variant pipeline for exome analyses (CONVEX) and the AION pipeline, followed by validation. Cross-referencing with existing genome-wide association study (GWAS) datasets identified two common variants, ISL1 and EFNA1, both of which are reported in European ancestry, suggesting a genetic architecture. Network analysis using Cytoscape and Cytohubba highlighted PKD1, PKD2, and PKHD1 as important hub genes and the 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 ARMs (SARMs), which may lead to improved genetic diagnosis and personalized interventions.