J G Seidman1, Christine E Seidman1, Sarah U Morton2, Alexandre C Pereira1, Daniel Quiat3, Felix Richter4, Alexander Kitaygorodsky5, Jacob Hagen5, Daniel Bernstein6, Martina Brueckner7, Elizabeth Goldmuntz8, Richard W Kim9, Richard P Lifton10, George A Porter11, Martin Tristani-Firouzi12, Wendy K Chung13, Amy Roberts3, Bruce D Gelb14, Yufeng Shen5, Jane W Newburger15. 1. Department of Genetics (A.C.P., J.G.S., C.E.S.), Harvard Medical School, Boston, MA. 2. Division of Newborn Medicine, Department of Medicine (S.U.M.), Boston Children's Hospital. 3. Department of Cardiology (D.Q., A.R., J.W.N.), Boston Children's Hospital. 4. Graduate School of Biomedical Sciences (F.R.), Icahn School of Medicine at Mount Sinai, New York, NY. 5. Departments of Systems Biology and Biomedical Informatics (A.K., J.H., Y.S.), Columbia University Medical Center, New York, NY. 6. Department of Pediatrics (Cardiology), Stanford University, CA (D.B.). 7. Departments of Genetics and Pediatrics, Yale University School of Medicine, New Haven, CT (M.B.). 8. Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, Univeristy of Pennsylvania (E.G.). 9. Cedars-Sinai Medical Center, Los Angeles, CA (R.W.K.). 10. Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY (R.P.L.). 11. Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, NY (G.A.P.). 12. Division of Pediatric Cardiology, University of Utah, Salt Lake City (M.T.-F.). 13. Departments of Pediatrics and Medicine (W.K.C.), Columbia University Medical Center, New York, NY. 14. Department of Pediatrics, Mindich Child Health and Development Institute (B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY. 15. Department of Pediatrics (S.U.M., D.Q., A.R., J.W.N.), Harvard Medical School, Boston, MA.
Abstract
BACKGROUND: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD. METHODS: DNV frequencies were determined for 1812 patients with CHD who had whole-genome sequencing and prenatal history data available from the Pediatric Cardiac Genomics Consortium's CHD GENES study (Genetic Network). The frequency of DNVs was compared between subgroups using t test or linear model. RESULTS: Among 1812 patients with CHD, the number of DNVs per patient was higher with maternal diabetes (76.5 versus 72.1, t test P=3.03×10-11), but the difference was no longer significant after including parental ages in a linear model (paternal and maternal correction P=0.42). No interaction was observed between diabetes risk and parental age (paternal and maternal interaction P=0.80 and 0.68, respectively). No difference was seen in DNV count per patient based on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal body mass index >30, t test P=0.86). CONCLUSIONS: After accounting for parental age, the offspring of diabetic or obese mothers have no increase in DNVs compared with other children with CHD. These results emphasize the role for other mechanisms in the cause of CHD associated with these prenatal exposures. REGISTRATION: URL: https://clinicaltrials.gov; NCT01196182.
BACKGROUND: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD. METHODS: DNV frequencies were determined for 1812 patients with CHD who had whole-genome sequencing and prenatal history data available from the Pediatric Cardiac Genomics Consortium's CHD GENES study (Genetic Network). The frequency of DNVs was compared between subgroups using t test or linear model. RESULTS: Among 1812 patients with CHD, the number of DNVs per patient was higher with maternal diabetes (76.5 versus 72.1, t test P=3.03×10-11), but the difference was no longer significant after including parental ages in a linear model (paternal and maternal correction P=0.42). No interaction was observed between diabetes risk and parental age (paternal and maternal interaction P=0.80 and 0.68, respectively). No difference was seen in DNV count per patient based on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal body mass index >30, t test P=0.86). CONCLUSIONS: After accounting for parental age, the offspring of diabetic or obese mothers have no increase in DNVs compared with other children with CHD. These results emphasize the role for other mechanisms in the cause of CHD associated with these prenatal exposures. REGISTRATION: URL: https://clinicaltrials.gov; NCT01196182.
Entities:
Keywords:
body mass index; genome; heart defects, congenital; obesity; prevalence
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