Abstract
Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development.
Highlights
Congenital heart defects (CHD) are the most common form of congenital malformations, affecting 0.8–1% of the population [1]
An interesting recent study using Mendelian Randomization (MR) proposed a new heritable form of risk for CHD originating from inherited extremes in the size of developing cardiovascular anatomy, where inheritance of a smaller diameter of the ascending aorta corresponded to an increase in risk for left ventricular outflow tract (LVOT) CHD [11]
Analyzing the phenotype and transcriptome of patient-derived human induced pluripotent stem cells (hiPSC) that have been differentiated to organotypic cells can pinpoint specific genes or molecular pathways involved in the disease processes
Summary
Congenital heart defects (CHD) are the most common form of congenital malformations, affecting 0.8–1% of the population [1]. 10% representing de novo genetic variants and 3–10% copy number variation [7,8]. Genetic factors have been identified to impact disease course [17,18,19], expanding the clinical significance of understanding their impact on CHD. The first genes associated with CHD were identified in 1998 by linkage analysis in families with multiple affected members. NOTCH1 was identified by linkage analysis to cause left ventricular outflow tract obstruction (LVOTO) defects and other CHD [21]. Chromosomal microarray is usually the first-line genetic test done in the clinical setting to identify CNVs in CHD with extracardiac anomalies and in individuals with conotruncal defects or type A interruption of the aortic arch as these can be the only early manifestation of 22q11-deletion syndrome
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