title: Allelic Interaction betweenCRELD1andVEGFAin the Pathogenesis of Cardiac Atrioventricular Septal Defects.
abstract: 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 inCRELD1. However,CRELD1mutations 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 functionalVEGFApolymorphism,VEGFAc.-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 theVEGFAc.-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 ofCRELD1andVEGFAgenotypes revealed that potentially pathogenic missense mutations inCRELD1were always accompanied by theVEGFAc.-634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used aCreld1knockout 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 inCRELD1and a functional SNP inVEGFAcontributes to the pathogenesis of AVSD.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Redig
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Gameil T
authors.initials: GT
authors.lastname: Fouad
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Darcie
authors.initials: D
authors.lastname: Babcock
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh PA 15261, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Reshey
authors.affiliation: Department of Physiology and the Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Maslen
keywords: congenital heart disease; genetic modifier