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Abstract
Atrioventricular septal defects (AVSD) are highly heritable, yet their genetic basis remains poorly understood. This study characterizes CRELD1 function using knockout mice and explores its interaction with VEGF in AVSD risk. Creld1(-/-) embryos exhibited early lethality with cardiovascular and endocardial cushion defects, implicating CRELD1 in heart development via apoptosis and vascular insufficiency. CRELD1(+/-) mice were normal, consistent with incomplete penetrance in humans. Genetic analysis revealed that VEGF-634C polymorphism strongly associates with AVSD and, combined with CRELD1 mutations, confers full penetrance. Functional assays confirmed CRELD1/VEGF interaction in abnormal cushion development, establishing the first proposed AVSD-risk profile.