Purpose of review: Atrioventricular septal defects (AVSDs) occur as a clinical feature of several different syndromes, as autosomal dominant defects, and as sporadically occurring malformations. Consequently, it is clear that there is genetic heterogeneity, but until recently, little else was known about the genes involved in the pathogenesis of AVSD. Recent advances in understanding the molecular genetic basis of AVSD are reviewed.

Recent findings: Atrioventricular septal defect is most often found associated with trisomy 21 (Down syndrome), but the responsible gene or genes on chromosome 21 have not been identified. However, promising candidates exist, and the current status of those efforts is presented. AVSD not associated with trisomy 21 usually occurs as a sporadic trait with no indication of the genetic basis. The discovery of cysteine rich with EGF domains (CRELD) 1 as the first recognized genetic risk factor for AVSD provides new insight into the genetic basis of sporadically occurring AVSD and the potential for genetic overlap with syndromic AVSD. Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient to cause the defect, indicating that AVSD is multigenic. Consequently, additional genes must be identified to understand the genetic basis of AVSD.

Summary: Because most nonsyndromic cases of AVSD are sporadic, opportunities for genetic analyses in humans are limited. An abundance of candidate genes have been identified through animal models and biochemical studies, but determining which actually contribute to the pathogenesis of AVSD will be difficult. Painstaking investigation of these candidate genes in humans may ultimately be necessary to identify the remaining genetic risk factors for AVSD.