Novel inherited CDX2 variant segregating in a family with diverse congenital malformations of the genitourinary system.

Anorectal malformations (ARM) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5,000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (Syndromic ARM) or as a non-syndromic entity (Non-syndromic ARM). Despite the well-recognized heritability of non-syndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies. Whole genome sequencing identified a novel paternally inherited heterozygous CDX2 variant (c.722A>G (p.Glu241Gly)), that was present in all 3 affected siblings. The variant identified in this family is absent from population databases and predicted to be damaging by most in silico pathogenicity tools. So far, only 2 other reports implicate variants in CDX2 with ARM. Remarkably, patients described in these studies exhibit similar clinical phenotypes and genetic alterations in CDX2. CDX2 encodes a transcription factor and is considered the master regulator of gastrointestinal development. This variant maps to the homeobox domain of the encoded protein, which is critical for interaction with DNA targets. Our finding provides a potential molecular diagnosis for our family's condition and supports the role of CDX2 in anorectal anomalies. It also highlights the clinical heterogeneity and variable penetrance of ARM predisposition variants, another well-documented phenomenon. Finally, it underscores the diagnostic utility of genomic profiling of ARM to identify the genetic etiology of these defects.