Abstract
Congenital heart disease (CHD) is the most common birth defect among newborns worldwide and contributes to significant infant morbidity and mortality. Owing to major advances in medical and surgical management, as well as improved prenatal diagnosis, the outcomes for these children with CHD have improved tremendously so much so that there are now more adults living with CHD than children. 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. For this reason, the complex process of cardiogenesis, which is governed by multiple interlinked and dose-dependent pathways, is a well investigated process. In addition to the sequence of the genome, the contribution of epigenetics to cardiogenesis is increasingly recognized. Significant progress has been made dissecting the epigenome of the heart and identified associations with cardiovascular diseases. The role of epigenetic regulation in cardiac development/cardiogenesis, using tissue and animal models, has been well reviewed. Here, we curate the current literature based on studies in humans, which have revealed associated and/or causative epigenetic factors implicated in CHD. We sought to summarize the current knowledge on the functional role of epigenetics in cardiogenesis as well as in distinct CHDs, with an aim to provide scientists and clinicians an overview of the abnormal cardiogenic pathways affected by epigenetic mechanisms, for a better understanding of their impact on the developing fetal heart, particularly for readers interested in CHD research.
Highlights
Congenital heart disease (CHD) refers to a heterogeneous collection of structural abnormalities of the heart or the great vessels present at birth
The methylation values of EGFR, EVC2, T-box 5 (TBX5) and CFC1B were significantly correlated with their mRNA levels, suggesting that aberrant promoter methylation of these CHD candidate genes may contribute to the Tetralogy of Fallot (TOF) development [83]
It is evident that transcriptional regulation plays a crucial role for normal cardiovascular development and that, if deranged, CHD may be a consequence
Summary
Congenital heart disease (CHD) refers to a heterogeneous collection of structural abnormalities of the heart or the great vessels present at birth. It is notable that for a large proportion of CHD, the severe forms, there is no other family history of CHD This underlies a significant contribution from de novo genetic events [9]. Whole exome and genome sequencing efforts reveal mutations in genes that contribute to CHD [17], but mutations in protein coding genes only account for 35% of CHD [9] Many of these protein coding genes are recognized as those encoding components of the epigenetic molecular pathways (e.g., histone modifying enzymes), underpinning a causality hypothesis for “molecular epigenetics”, or pathways that regulate networks of gene expression [9].
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