Human Genetics of Atrioventricular Septal Defect

Atrioventricular septal defects (AVSD), also known as a common atrioventricular canal (CAVC), are clinically severe heart malformations that affect about 1 out of every 2100 live births. AVSD makes up about 5% of all congenital heart defects. AVSD is associated with cytogenetic disorders such as Down syndrome and numerous other rare genetic syndromes, but also occurs as a simplex trait. Studies in mouse models have identified over 100 genetic mutations that have the potential to cause an AVSD. However, studies in humans indicate that AVSD is genetically heterogeneous, and that the cause in humans is very rarely a single-gene defect. Familial cases do occur albeit rarely, usually with autosomal dominant inheritance and variable expression. In addition, the frequent occurrence of AVSD in some syndromes with known genetic causes such as heterotaxy syndrome points to additional genes/pathways that increase AVSD risk. Accordingly, while the genetic underpinnings for most AVSD remain unknown, there have been advances in identifying genetic risk factors for AVSD in both syndromic and nonsyndromic cases. This chapter summarizes the current knowledge of the genetic basis for AVSD.