Rare variants in TTC7A, ROCK2 and LIMK2 suggest a role for the ROCK-signaling pathway in isolated intestinal malrotation.

PURPOSE: This study aimed to identify genetic variants contributing to the development of early-diagnosed isolated intestinal malrotation.

METHODS

We conducted Genome sequencing on ten young children diagnosed with midgut volvulus due to intestinal malrotation who presented no other malformations or comorbidities. Our analysis focused on a panel of 442 genes previously associated with intestinal development, malrotation, ciliopathies and/or situs abnormalities.

RESULTS

In one male patent we discovered two heterozygous variants in TTC7A, c.433G > A p.(Ala145Thr) and c.1057G > A p.(Glu353Lys). Carrier testing revealed that he inherited both variants from his mother with a mild intestinal rotation abnormality. Additionally, we identified inherited variants in two other male participants, c.1802 A > T p.(Asp601Val) in ROCK2 and, c.884 G > A p.(Arg295His) in LIMK2. These genes are part of a shared signaling pathway previously shown to cause intestinal malrotation in Xenopus when inhibited.

CONCLUSION

Our findings suggest the potential involvement of TTC7A, ROCK2 and LIMK2-genes in the pathogenesis of intestinal malrotation; through the ROCK-signaling pathway.