Here we investigate the co-segregation of CRELD1 missense mutations and the VEGFA c.–634C allele in individuals with simplex AVSD, and characterize an interaction between CRELD1 and VEGFA in the developing heart as a possible contributing mechanism in the pathogenesis of this clinically significant heart malformation. The gene discussed is CRELD1; the disease is familial atrioventricular septal defect.