Molecular genetic mechanisms of congenital heart disease

Abstract

Congenital heart disease (CHD) affects ~1% of all live births, but a definitive etiology is identified in only ~50%. The causes include chromosomal aneuploidies and copy-number variations, pathogenic variation in single genes, and exposure to environmental factors. High-throughput sequencing of large CHD patient cohorts and continued expansion of the complex molecular regulation of cardiac morphogenesis has uncovered numerous disease-causing genes, but the previously held monogenic model for CHD etiology does not sufficiently explain the heterogeneity and incomplete penetrance of CHD phenotypes. Here, we provide a summary of well-known genetic contributors to CHD and discuss emerging concepts supporting complex genetic mechanisms that may provide explanations for cases that currently lack a molecular diagnosis.

Conflict of interest statement

Declaration of Interest

The authors declare no conflict of interest.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Key stages and regulatory genes in mouse cardiac development.

At embryonic day (E) 7.5, the first heart field (FHF) progenitors, followed closely by the second heart field (SHF) progenitors, become spatially organized into the cardiac crescent at the anterolateral plate of the developing embryo. At ~8.0, these cells migrate to the ventral midline and fuse together to form a linear heart tube containing an inner endocardial lining. The heart tube undergoes rightward looping and begins segmenting into the common atria and common ventricles. Furthermore, endothelial-to-mesenchymal transformation proceeds in the atrioventricular canal (AVC) and outflow tract (OFT) along with neural crest cell migration to the OFT. Subsequently, complete septation of the heart gives rise to four distinct chambers as well as the aorta (Ao) and pulmonary artery (PA) and further remodeling of endocardial cushions lead to the atrioventricular and semilunar valves. A partial list of key cardiac regulatory genes at each stage is shown. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; IVS, interventricular septum. Created with Biorender.com.

Figure 2.. Molecular genetic mechanisms underlying CHD.

Chromosomal aberrations, disrupted chromatin organization, altered epigenetic mechanisms, environmental factors and pathogenic variation represent identified mechanisms for CHD. Additional molecular etiologies for CHD pathogenesis are shown (where TBX5 serves as a representative example) and include oligogenic inheritance of variation in both TBX5 and MEF2C, which represent interconnected nodes in a gene regulatory network, and pathogenic variation in noncoding elements regulating TBX5. The schematic also represents how a subset of these factors could interact in a multifactorial manner to cause CHD. Created with Biorender.com.