DNA methylation abnormalities in congenital heart disease

Abstract

Congenital heart defects represent the most common malformation at birth, occurring also in »50% of individuals with Down syndrome. Congenital heart defects are thought to have multifactorial etiology, but the main causes are largely unknown. We have explored the global methylation profile of fetal heart DNA in comparison to blood DNA from control subjects: an absolute correlation with the type of tissue was detected. Pathway analysis revealed a significant enrichment of differential methylation at genes related to muscle contraction and cardiomyopathies in the developing heart DNA. We have also searched for abnormal methylation profiles on developing heart-tissue DNA of syndromic and non-syndromic congenital heart defects. On average, 3 regions with aberrant methylation were detected per sample and 18 regions were found differentially methylated between groups. Several epimutations were detected in candidate genes involved in growth regulation, apoptosis and folate pathway. A likely pathogenic hypermethylation of several intragenic sites at the MSX1 gene, involved in outflow tract morphogenesis, was found in a fetus with isolated heart malformation. In addition, hypermethylation of the GATA4 gene was present in fetuses with Down syndrome with or without congenital heart defects, as well as in fetuses with isolated heart malformations. Expression deregulation of the abnormally methylated genes was detected. Our data indicate that epigenetic alterations of relevant genes are present in developing heart DNA in fetuses with both isolated and syndromic heart malformations. These epimutations likely contribute to the pathogenesis of the malformation by cis-acting effects on gene expression.

MTHFR promoter hypermethylation may lead to congenital heart defects in Down syndrome

“…A case-control study from Spain reported absence of maternal folic acid supplementation was more frequent in DS with atrioventricular septal defects (OR = 1.69, 95% CI = 1.08 -2.63) or atrial septal defects (OR = 1.69, 95% CI= 1.11 -2.58) compared to DS without CHD (18). Thus, maternal supplementation with folic acid is likely to be associated with reduced risk of CHD in DS.…”

Efficiency of Methylated DNA Immunoprecipitation Bisulphite Sequencing for Whole-Genome DNA Methylation Analysis

“…In particular, DNA methylation is closely associated with gene expression regulation, and it is well-known that aberrant DNA methylation may contribute to the occurrence of various diseases such as heart disease [20], Alzheimer's disease [21] and cancer [22,23]. The development of NGS technology has accelerated genetics and epigenetics research, concomitantly advancing the development of diverse DNA methylation analysis technologies.…”

Determining the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and genomic DNA methylation level: A meta‐analysis

“…In recent years, population and experimental studies have provided evidence to support the role of folate metabolism in healthy development, through regulation of methylation modifications of the genome (Crott et al, 2008;Wang et al, 2010;Crider et al, 2012;Serra-Juhe et al, 2015). MTHFR genotypes are believed to alter folate metabolism in cells (Kim et al, 2010;Tsang et al, 2015) and subsequently modify methylation.…”