| Summary: | Congenital heart defect (CHD) is a rare and complicated disease with a high mortality rate. Its etiology remains unclear and includes many aspects. DNA methylation has been indicated to be involved in heart development in the early stage of life, and aberrant methylation level was related to CHDs. This study provides the first evidence of the cross talk of SNP variants and DNA methylation in clarifying CHD underlying genomic cause. We gathered whole exome sequencing (WES) data for Group 1 consisting of patients with PA (n = 78), TOF (n = 20), TAPVC (n = 78), and PDA (n = 40), and 100 healthy children as control group. Rare non-synonymous mutations and novel genes were found and highlighted. Meanwhile, we carried out the second analysis of DNA methylation data from patients with PA (n = 3), TAPVC (n = 3), TOF (n = 3), and PDA (n = 2), and five healthy controls using 850 K array in Group 2. DNA methylation was linked to WES data, and we explored an obvious overlap of hyper/hypomethylated genes. Next, we identified some candidate genes by Fisher’s exact test and Burden analysis; then, those methylated genes were figured out by the criteria of the mutation located in the CpG islands of the genome, differential methylation sites (DMS), and DNA methylation quantitative trait loci (meQTLs) in the database, respectively. Also, the interaction of differentially methylated candidate genes with known CHD pathogenetic genes was depicted in a molecular network. Taken together, our findings show that nine novel genes (ANGPTL4, VEGFA, PAX3, MUC4, HLA-DRB1, TJP2, BCR, PKD1, and HK2) in methylation level are critical to CHD and reveal a new insight into the molecular pathogenesis of CHD.
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