Abstract
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.
Highlights
Tetralogy of Fallot (TOF) is marked by a constellation of anatomical findings, including ventricular septal defect (VSD), pulmonary stenosis (PS), right ventricular hypertrophy and an overriding aorta
High predictive accuracy for TOF detection was achieved at multiple CpG targets (Fig 1)
The False Discovery Rate (FDR) p-values for the methylation difference between TOF subjects and controls were highly significant
Summary
Tetralogy of Fallot (TOF) is marked by a constellation of anatomical findings, including ventricular septal defect (VSD), pulmonary stenosis (PS), right ventricular hypertrophy and an overriding aorta. In the United States, the prevalence of TOF is estimated at 3.9 per 10,000 live births [1] and it accounts for 7–10% of congenital heart defect (CHD) cases. TOF the most common critical congenital heart defect (CCHD) defined as CHDs that require surgical or other significant medical intervention before one year of age.[2]. Prenatal and newborn diagnosis is, pivotal to reducing morbidity and mortality in CHD. A recent population-based screening study reported that nearly half of major CHD cases are missed on prenatal screening [3], this is consistent with other population- based studies reported in the literature. The current standard of care requires pulse oximetry screening of all newborns to detect CCHDs [5,6,7]. Simulation models suggest only modest detection rates for TOF using pulse oximetry screening.[9]
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