Familial currarino syndrome caused by a deep intronic variant resulting in missplicing of MNX1

Currarino syndrome (CS) is an autosomal dominant multiple congenital anomalies syndrome characterised by a triad of anorectal malformations, presacral masses, and sacral defects. To date, pathogenic variants in only one gene, MNX1, have been shown to cause the condition. However, a causative variant at this locus is identified in only half of clinically diagnosed individuals. We report a three-generation family with CS and perform whole-genome sequencing to investigate potential causative variants after an initial exonic screen of MNX1 was negative for an explanatory factor. We identify a novel deep intronic MNX1 variant located in intron 2 that segregates with the phenotype. Using a transfection-based gene splicing assay, we demonstrate that this variant subverts normal splicing of MNX1. These findings suggest that similar non-coding variants should be sought in MNX1 when exonic evaluation has not yielded a diagnostic explanation for a CS presentation.