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.