Abstract
Ventricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue crucial in cardiac development and a potentially useful surrogate for evaluating the development of heart tissue. To understand epigenetic mechanisms that may play a role in the development of VSD, genome-wide DNA methylation assay on placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 unaffected controls was performed using the Illumina HumanMethylation450 BeadChip assay. We identified a total of 80 highly accurate potential CpGs in 80 genes for detection of VSD; area under the receiver operating characteristic curve (AUC ROC) 1.0 with significant 95% CI (FDR) p-values < 0.05 for each individual locus. The biological processes and functions for many of these differentially methylated genes are previously known to be associated with heart development or disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). In addition, we identified 8 microRNAs that have the potential to be biomarkers for the detection of VSD including: miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting VSD.
Highlights
Congenital Heart Defect (CHD) affects nearly 40,000 newborns per year in the United States [1,2]
Genome-wide DNA methylation analysis of placenta-derived DNA was performed on 8 Ventricular Septal Defect (VSD) cases and 10 unaffected controls
Total of 1248 loci had good diagnostic accuracy defined as Area Under Curve (AUC) 0.81 to 0.99 for VSD detection
Summary
Congenital Heart Defect (CHD) affects nearly 40,000 newborns per year in the United States [1,2]. Ventricular Septal Defect (VSD) is the most common congenital heart disease (CHD) and occurs in approximately 1 in 500 live births [3,4,5]. Common risk factors for VSD include family history, ethnicity, and a few genetic disorders. Targeted disruption of the CHF1/Hey locus in mice resulting in VSD has been reported [8]. Despite these known genetic disruptions, in the clinical setting the cause of VSD remains unknown in the great majority of cases
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