Identification of Potential Causative Gene of Anorectal Malformation

Anorectal malformations (ARM) constitute a heterogeneous group of rare congenital anomalies affecting the cloaca. Although genetic factors are implicated in ARM pathogenesis, our understanding of the underlying molecular mechanisms remains limited for both non-syndromic and syndromic ARM. Despite recent advancements, the genes identified so far account for only about 30% of the diagnostic yield from exome sequencing. Our study aimed to identify potential novel disease-causing mutations associated with ARMs. We performed exome sequencing on 12 patients with ARM and discovered a pathogenic single nucleotide polymorphism (SNP) in the MFHAS1 gene in two individuals with non-syndromic ARM. Additionally, we identified insertion/deletion (INDEL) and splice-site variants in five genes - SOX9, AOC4P, SKA3, KRTAP5-7, and PRSS2. Despite the insights provided by our study regarding the association of these variants with ARM occurrence, further functional and segregation studies in larger cohorts are necessary to validate these findings.