Genetics and Genomics of Congenital Heart Disease

Abstract

Congenital heart disease is the most common birth defect, and because of major advances in medical and surgical management, there are now more adults living with congenital heart disease (CHD) than children. Until recently, the cause of the majority of CHD was unknown. Advances in genomic technologies have discovered the genetic causes of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. This review will focus on the evidence for genetic causes underlying CHD and discuss data supporting both monogenic and complex genetic mechanisms underlying CHD. The discoveries from CHD genetic studies draw attention to biological pathways that simultaneously open the door to a better understanding of cardiac development and affect clinical care of patients with CHD. Finally, we address clinical genetic evaluation of patients and families affected by CHD.

Keywords: genetics; genome; human; life; technology.

Figure 1

A Outline of human heart development. The X axis displays days of human and mouse gestation. B The spectrum of congenital heart disease from mild to severe. The lesions indicated as “severe” are expected to require intervention in the first year of life. ASD-Atrial Septal Defect, VSD-Ventricular Septal Defect, CoA- Coarctation of the Aorta, TOF-Tetralogy of Fallot, TGA- Transposition of the Great Arteries, HLHS- Hypoplastic Left Heart Syndrome. Classes of CHD based on proposed developmental-genetic mechanisms are indicated in parentheses; LVO-Left Ventricular Outflow Obstruction, CTD- Cono-Truncal Defect, HTX- Heterotaxy. C Genetic causes of CHD identified to date.

Figure 2

Chromatin remodeling genes in CHD. A Chromatin remodeling genes with mutations identified in CHD patients to date, highlighting the overlap between CHD and NDD genes. Nucleosomes with H3K4, H3K9, H3K27, H3K36 and H4K20 methylation and/or acetylation, and H2BK120 ubiquitylation are shown (adapted from Homsy et al, Science 2015). B Syndromes associated with chromatin remodeling gene mutations and their associated CHD and neurodevelopmental abnormalities.

Figure 3

NOTCH signaling in CHD A outline of NOTCH signaling pathway showing signal-sending cell in yellow, and signal receiving cell in green. B Syndromes and CHD associated with NOTCH pathway gene mutations.

Figure 4

Cilia in CHD A Diagram of a cilium, showing the ciliary axoneme (blue) based on the mother centriole (gray) and linked via the transition zone (orange). B Syndromes and CHD linked to human cilia mutations.

Figure 5

Outline of proposed clinical genetic testing for patients with CHD