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Nat Genet. 2017 Nov;49(11):1593-1601. doi: 10.1038/ng.3970. Epub 2017 Oct 9.

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

Author information

1
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
3
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
4
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.
5
Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
6
Department of Applied Physics and Applied Mathematics, Columbia University, New York, New York, USA.
7
Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
8
Department of Computational Chemistry, University College London School of Pharmacy, London, UK.
9
Yale Center for Genome Analysis, Yale University, New Haven, Connecticut, USA.
10
Department of Psychiatry, University of California San Francisco, San Francisco, California, USA.
11
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
12
Division of Pediatric Cardiology, University of Michigan, Ann Arbor, Michigan, USA.
13
Department of Pediatric Cardiac Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
14
Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK.
15
Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, New York, USA.
16
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
17
Roddenberry Stem Cell Center at Gladstone, San Francisco, California, USA.
18
Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, San Francisco, California, USA.
19
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
20
Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, New York, USA.
21
Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah and School of Medicine, Salt Lake City, Utah, USA.
22
USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, Utah, USA.
23
Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah, USA.
24
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
25
Pediatric Cardiac Surgery, Children's Hospital of Los Angeles, Los Angeles, California, USA.
26
Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, Maryland, USA.
27
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
28
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, USA.
29
Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
30
Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts, USA.
31
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York, USA.
32
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.

Abstract

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

PMID:
28991257
PMCID:
PMC5675000
DOI:
10.1038/ng.3970
[Indexed for MEDLINE]
Free PMC Article

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