The Role of Epigenetics in Congenital Heart Disease

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.

Epidemiology, Genetics and Epigenetics of Congenital Heart Diseases in Twins

“…An insight into congenital cardiac abnormalities can be gained by analyzing the epigenetic pathways in identical discordant twins [55,56]. Understanding the factors that cause molecular plasticity is difficult but it will add to our present understanding of CHD [56].…”

“…An insight into congenital cardiac abnormalities can be gained by analyzing the epigenetic pathways in identical discordant twins [55,56]. Understanding the factors that cause molecular plasticity is difficult but it will add to our present understanding of CHD [56]. In many investigations of the heart's differential methylation profile, the tissue level is used rather than the cell level [57].…”

“…However, this is not ideal as analysis at tissue level may overlook numerous differentially methylated genes [57]. This problem is fixed by the single-cell DNA methylation sequencing technique, which helps identify stage-specific issues in signals and regulatory pathways of cardiogenesis [56,57]. Because of the lack of access to human cardiac tissue during the early stages of cardiogenesis, bulk sequencing investigations (e.g., transcriptomics) have been performed on cardiac tissues obtained from terminated fetuses or surgical samples [56].…”

From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

“…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 ]. In addition to genetic variations, nsCHD risk factors include epigenetic changes [ 12 ] and adverse environmental stimuli, such as maternal glycemic dysregulation, obesity, and certain medications and infections during pregnancy [ 13 , 14 , 15 , 16 ].…”

“…Genes 2021, 12, 921 2 of 13 New technologies have paved the way to an improved understanding of CHD. Nextgeneration sequencing and genome-wide association studies (GWAS) have expanded our understanding of the etiological factors of CHD.…”