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PLoS One. 2018 Sep 13;13(9):e0203893. doi: 10.1371/journal.pone.0203893. eCollection 2018.

Newborn blood DNA epigenetic variations and signaling pathway genes associated with Tetralogy of Fallot (TOF).

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


Tetralogy of Fallot (TOF) is the most common Critical Congenital Heart Defect (CCHD). The etiology of TOF is unknown in most cases. Preliminary data from our group and others suggest that epigenetic changes may play an important role in CHD. Epidemiologically, a significant percentage of CHD including TOF fail to be diagnosed in the prenatal and early newborn period which can negatively affect health outcomes. We performed genome-wide methylation assay in newborn blood in 24 non-syndromic TOF cases and 24 unaffected matched controls using Illumina Infinium HumanMethylation450 BeadChips. We identified 64 significantly differentially methylated CpG sites in TOF cases, of which 25 CpG sites had high predictive accuracy for TOF, based on the area under the receiver operating characteristics curve (AUC ROC) ≥ 0.90). The CpG methylation difference between TOF and controls was ≥10% in 51 CpG targets suggesting biological significance. Gene ontology analysis identified significant biological processes and functions related to these differentially methylated genes, including: CHD development, cardiomyopathy, diabetes, immunological, inflammation and other plausible pathways in CHD development. Multiple genes known or plausibly linked to heart development and post-natal heart disease were found to be differentially methylated in the blood DNA of newborns with TOF including: ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9. We generated novel and highly accurate putative molecular markers for TOF detection using leucocyte DNA and thus provided information on pathogenesis of TOF.

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