Functional genomics in Xenopus identifies ARHGAP10 as a congenital heart disease and ciliopathy gene.

Congenital heart disease (CHD) remains a major cause of pediatric morbidity and mortality, yet many patients lack a genetic diagnosis. Two studies identified rare deletions in ARHGAP10 (GAP10), a Rho GTPase-activating protein at 4q31.2 in individuals with heterotaxy and atrial septal defects, highlighting GAP10 as a new candidate CHD gene; however, the function of GAP10 has not been investigated. We demonstrate that gap10 deletion disrupts body axis extension, left-right organizer (LRO) formation, and ciliogenesis, leading to severe cardiac looping defects that closely mirror human CHD phenotypes in Xenopus. Gap10 localizes to basal bodies of motile cilia in multiciliated cells, where it regulates basal body and apical F-actin organization by recruiting focal adhesion kinase (FAK) to specialized ciliary-adhesion complexes. Our findings implicate GAP10 as a clinically relevant, genetically supported, and functionally validated regulator of CHD and ciliogenesis, underscoring the power of functional genomics for discovering rare disease genes.