Allelic Interaction between and in the Pathogenesis of Cardiac Atrioventricular Septal Defects.

Atrioventricular septal defects (AVSD) are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5-10% of simplex AVSD cases carry a missense mutation in . However, mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA) is a well-characterized modulator of heart valve development. A functional polymorphism, c.-634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the c.-634 SNP in a simplex AVSD study cohort. Over-representation of the c.-634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of and genotypes revealed that potentially pathogenic missense mutations in were always accompanied by the c.-634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in and a functional SNP in contributes to the pathogenesis of AVSD.