Genetic Pathways in Congenital Heart Development

Abstract

Congenital heart disease (CHD) is the most common birth defect in newborns. Although insights into the genes and pathways involved that cause CHD have been identified by targeted perturbations of molecules that function in the developmental pathways involved in myocyte specification, differentiation or cardiac morphogenesis, the direct role of these or other perturbations in humans has remained poorly understood. Researchers have tried to bridge this knowledge gap through conventional genome‐wide analyses of rare Mendelian CHD families and by sequencing candidate genes in CHD cohorts. While these discoveries have yield highly penetrant inherited mutations in families with mild to moderately severe CHD, analyses of these genes rarely defines a pathogenic mutation in severe forms of CHD that occurs as a sporadic event, the most common presentation of CHD. The advent of contemporary genomic technologies including SNP arrays, next‐generation sequencing, and CNV analyses are accelerating the discovery of genetic causes of severe and sporadic CHD. Remarkably, emerging genomic data have validated and extended earlier observations leaned from the experimental CHD models and monogenic CHD families. Together these dataset have begun to define the genetic architecture of CHD: CHD gene encode molecules that orchestrate cardiac development; CHD mutations alter gene/protein dosage; comparable CHD mutations yield many distinct malformations, implying that higher order interactions account for particular CHD phenotypes.