Integrative Functional Genomics Identifies ARHGAP10 in the 4q31.2 Locus as a Novel Congenital Heart Disease and Ciliopathy Gene.
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Congenital heart disease (CHD) remains a major cause of pediatric morbidity and mortality, yet its genetic underpinnings are not fully understood. Two studies independently identified rare deletions in ARHGAP10 (GAP10), a Rho GTPase-activating protein located at 4q31.2 in individuals with heterotaxy and atrial septal defects (n=2 rare copy number variants (CNVs)), highlighting GAP10 as a new candidate CHD gene. While the 4q31.2 locus is implicated in CHD, the function of GAP10 has not been investigated. Here, using Xenopus tropicalis as a model, we demonstrate that gap10 deletion disrupts morphogenetic movements critical for body axis extension, left-right organizer (LRO) formation, and ciliogenesis, leading to severe cardiac looping defects that closely mirror human CHD phenotypes. Moreover, gap10 localizes to basal bodies of motile cilia in multiciliated cells, where it regulates basal body organization and apical actin enrichment by recruiting focal adhesion kinase (FAK) to specialized ciliary adhesion complexes. In summary, our findings implicate GAP10 as a clinically relevant, genetically supported, and functionally validated regulator of CHD and ciliogenesis, underscoring the power of integrative functional genomics in the discovery of rare disease genes.
