Novel inheritedCDX2variant segregating in a family with diverse congenital malformations of the genitourinary system

• DOI: 10.1101/mcs.a006294
• Publication Date: 2023-10-10T19:20:40Z
• Authors: Swetha Ramadesikan; Caitlyn M. Colwell; Rachel Supinger; Jesse Hunter; Jessica Thomas; Elizabeth Varga; Elaine R. Mardis; Richard J. Wood; Daniel C. Koboldt
• Keywords: Penetrance

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