Genetics and Genetic Testing in Congenital Heart Disease

Abstract

Congenital heart defects (CHDs) are structural abnormalities of the heart and great vessels that are present from birth. The presence or absence of extra-cardiac anomalies has historically been used to identify patients with possible monogenic, chromosomal, or teratogenic CHD etiologies. These distinctions remain clinically relevant, particularly with regard to management; however, identification of genetic causes in patients with presumably non-syndromic CHD indicates that isolated CHD can also be genetic in origin. In recent years, the field of cardiac genetics has benefited from a growing understanding of the complex molecular mechanisms underpinning heart development, and the extreme genetic heterogeneity of CHD is increasingly appreciated. Progress has been largely supported by improvements in genetic testing technology derived from worldwide efforts to accurately and economically characterize the full breadth of human genomic variation. The last fifteen years in particular have witnessed emergence and refinement of novel cytogenetic and sequencing technologies, which have proven to be enormously effective tools for both diagnosis and identification of novel CHD-causing genes. These advancements have led to an increasing need for cardiac care providers to be well versed in the molecular genetic origins of CHD and to have working knowledge of the benefits and limitations of available testing methods. In this review, we provide a general overview of key morphologic, molecular, and signaling mechanisms relevant to heart development before summarizing overall progress in the molecular genetic analyses of CHDs and current recommendations for clinical application of genetic testing. Particular emphasis is placed on the utility and limitations of chromosomal microarray analyses (CMAs) and on emerging clinical roles for whole exome sequencing (WES) and other next-generation sequencing (NGS) technologies.