Genetic Basis of Human Congenital Heart Disease

Abstract

Congenital heart disease (CHD) is the most common major congenital anomaly with an incidence of ∼1% of live births and is a significant cause of birth defect-related mortality. The genetic mechanisms underlying the development of CHD are complex and remain incompletely understood. Known genetic causes include all classes of genetic variation including chromosomal aneuploidies, copy number variants, and rare and common singlenucleotide variants, which can be either de novo or inherited. Among patients with CHD, ∼8%-12% have a chromosomal abnormality or aneuploidy, between 3% and 25% have a copy number variation, and 3%-5% have a single-gene defect in an established CHD gene with higher likelihood of identifying a genetic cause in patients with nonisolated CHD. These genetic variants disrupt or alter genes that play an important role in normal cardiac development and in some cases have pleiotropic effects on other organs. This work reviews some of the most common genetic causes of CHD as well as what is currently known about the underlying mechanisms. C ongenital heart disease (CHD) is the most common major congenital anomaly with an incidence of ∼1% of live births (Hoffman and Kaplan 2002; Calzolari et al. 2003). CHD is a significant cause of birth defect-related mortality (

Conditional inactivation of Foxc1 and Foxc2 in neural crest cells leads to cardiac abnormalities

“…Foxc1 and Foxc2 are closely related members of the Fox transcription factor family and have numerous essential roles in cardiovascular development, including the formation of the cardiac OFT (Kume, Jiang, Topczewska, & Hogan, 2001;. Mutations in human FOXC1 and FOXC2 are associated with cardiac OFT malformations such as Tetralogy of Fallot (Majumdar, Yasuhara, & Garg, 2019;Nees & Chung, 2019;Topf et al, 2014). Our previous studies reveal that the expression patterns of Foxc1 and Foxc2 in mice are overlapped in the developing heart, including cNCCs as well as their derivatives in the OFT cushion that contribute to the OFT septum (Iida et al, 1997;Inman et al, 2018;Winnier et al, 1999).…”

What is the impact of a novel MED12 variant on syndromic conotruncal heart defects? Analysis of case report on two male sibs

“…Causes of CHDs are genetic in 8%, environmental in 2% and multifactorial or not determined in about 90% of cases [7]. The genetic mechanisms responsible for CHD are complex, heterogeneous and incompletely understood: approximately 8-12% is due to chromosomal anomalies, 3-25% to copy number variation and 3-5% to single gene defect [8]. These genetic variants, de novo or inherited, concern genes involved in normal cardiac development, altering signal transduction, transcriptional regulation and encoding proteins.…”

“…These genetic variants, de novo or inherited, concern genes involved in normal cardiac development, altering signal transduction, transcriptional regulation and encoding proteins. In some cases the same genes have pleiotropic effects on other organs [8] and this explains syndromic CHDs.…”

Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

“…Pathogenic variants linked to isolated CHD primarily encode transcription factors, signaling molecules, structural proteins and epigenetic modifiers that are essential for normal cardiac development ( Zaidi et al, 2013 ; Pierpont et al, 2018 ; Nees and Chung, 2019 ; Table 1 ). For instance, genetic variants in highly conserved transcription factors critical for cardiac development are found in both familial and sporadic cases of CHD.…”

“…Congenital heart disease (CHD) is a leading cause of birth defect-related death and affects ∼1% of live births in the United States ( Hoffman and Kaplan, 2002 ; Nees and Chung, 2019 ). CHD is characterized by morphological abnormalities in the cardiac chambers, septa and valves as well as the great vessels arising from the heart.…”