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PLoS One. 2019 Mar 21;14(3):e0200229. doi: 10.1371/journal.pone.0200229. eCollection 2019.

Placental epigenetics for evaluation of fetal congenital heart defects: Ventricular Septal Defect (VSD).

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Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, United States of America.
Department of Obstetrics and Gynaecology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
Department of Obstetrics and Gynaecology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
Department of Studies in Genetics and Genomics, Laboratory of Genomic Sciences, University of Mysore, Mysore, India.
Biotechnology, Nirma Institute of Science, Nirma University, Ahmedabad, India.
Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Centre Omaha, Nebraska, United States of America.


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.

Conflict of interest statement

The authors have declared that no competing interests exist.

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