Abstract
Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.
Highlights
Congenital heart disease (CHD) is a collective diagnosis for structural malformations of the heart and great vessels [1]
CHD patients whose disease occurs with additional phenotypes such as neurodevelopmental disabilities (NDD) or extracardiac abnormalities (ECA), or in whom the CHD is part of a known syndrome, tend to feature distinct genetics compared with patients with isolated CHD [17]
The first application of whole-exome sequencing (WES) to systematically assess the impact of de novo single nucleotide variants and small insertions/deletions on CHD sequenced 362 trios (CHD patients and their parents) and used a case-control setup to show that CHD patients are relatively enriched for de novo mutations (DNMs) in genes highly expressed in the developing heart (HHE genes) [8]
Summary
Congenital heart disease (CHD) is a collective diagnosis for structural malformations of the heart and great vessels [1]. The first year of life features the majority of fatalities attributable to CHD, and the probability of surviving into adulthood increases to at least 75% after age one [29]. CHD patients tend to experience higher rates of adverse health events compared to aged individuals in the general population [29]. Some of these events, such as reversal of left-to-right shunts with Eisenmenger syndrome, are directly predicted by principles of physiology. Other adverse health events in CHD are likely linked to the genetic etiology, such as the elevated lifetime risk of cancer among CHD patients [15]. CHD patients whose disease occurs with additional phenotypes such as neurodevelopmental disabilities (NDD) or extracardiac abnormalities (ECA), or in whom the CHD is part of a known syndrome, tend to feature distinct genetics compared with patients with isolated CHD [17]
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