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PMID: 26785492 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

Science (New York, N.Y.) ·Vol. 350 ·No. 6265 ·2015-12-04 ·Pages 1262-6

Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, Jin SC, Deanfield J, Giardini A, Porter GA, Kim R, Bilguvar K, López-Giráldez F, Tikhonova I, Mane S, Romano-Adesman A, Qi H, Vardarajan B, Ma L, Daly M, Roberts AE, Russell MW, Mital S, Newburger JW, Gaynor JW, Breitbart RE, Iossifov I, Ronemus M, Sanders SJ, Kaltman JR, Seidman JG, Brueckner M, Gelb BD, Goldmuntz E, Lifton RP, Seidman CE, Chung WK

Abstract

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

MeSH Terms
Brain/abnormalities,metabolism Child Congenital Abnormalities/genetics Exome/genetics Heart Defects, Congenital/diagnosis,genetics Humans Mutation Nervous System Malformations/genetics Neurogenesis/genetics Prognosis RNA Splicing/genetics RNA Splicing Factors RNA, Messenger/genetics RNA-Binding Proteins/genetics Repressor Proteins/genetics Transcription, Genetic
Chemicals
RBFOX2 protein, human RNA Splicing Factors RNA, Messenger RNA-Binding Proteins Repressor Proteins
Authors & Affiliations
41 authors, click to expand affiliations / ORCID
Homsy Jason
Department of Genetics, Harvard Medical School, Boston, MA, USA. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Zaidi Samir
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Shen Yufeng
Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
Ware James S
Department of Genetics, Harvard Medical School, Boston, MA, USA. NIHR Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation and Trust and Imperial College London, London, UK. National Heart & Lung Institute, Imperial College London, London, UK.
Samocha Kaitlin E
Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA.
Karczewski Konrad J
Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA.
DePalma Steven R
Department of Genetics, Harvard Medical School, Boston, MA, USA. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA.
McKean David
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Wakimoto Hiroko
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Gorham Josh
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Jin Sheng Chih
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Deanfield John
Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK.
Giardini Alessandro
Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK.
Porter George A
Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, NY, USA.
Kim Richard
Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Bilguvar Kaya
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
López-Giráldez Francesc
Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
Tikhonova Irina
Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
Mane Shrikant
Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
Romano-Adesman Angela
Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA.
Qi Hongjian
Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, USA. Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY, USA.
Vardarajan Badri
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Ma Lijiang
Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
Daly Mark
Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA.
Roberts Amy E
Department of Cardiology, Children's Hospital Boston, Boston, MA, USA.
Russell Mark W
Division of Pediatric Cardiology, University of Michigan, Ann Arbor, MI, USA.
Mital Seema
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Newburger Jane W
Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
Gaynor J William
Department of Pediatric Cardiac Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Breitbart Roger E
Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
Iossifov Ivan
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Ronemus Michael
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Sanders Stephan J
Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
Kaltman Jonathan R
Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, MD, USA.
Seidman Jonathan G
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Brueckner Martina
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. [email protected] [email protected] [email protected] [email protected] [email protected] [email protected].
Gelb Bruce D
Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected] [email protected] [email protected] [email protected] [email protected] [email protected].
Goldmuntz Elizabeth
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected] [email protected] [email protected] [email protected] [email protected] [email protected].
Lifton Richard P
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. [email protected] [email protected] [email protected] [email protected] [email protected] [email protected].
Seidman Christine E
Department of Genetics, Harvard Medical School, Boston, MA, USA. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA. Cardiovascular Division, Brigham & Women's Hospital, Harvard University, Boston, MA, USA. [email protected] [email protected] [email protected] [email protected] [email protected] [email protected].
Chung Wendy K
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA. [email protected] [email protected] [email protected] [email protected] [email protected] [email protected].
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aac9396
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Published
2015-12-04
Pages
1262-6
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC4890146
Subset
IM
Grants
NHLBI NIH HHS · UM1 HL098162 · United States
British Heart Foundation · United Kingdom
NHLBI NIH HHS · U01 HL098162 · United States
NHLBI NIH HHS · T32 HL007208 · United States
NHLBI NIH HHS · UM1 HL098166 · United States
Medical Research Council · MC_UP_1102/20 · United Kingdom
NIGMS NIH HHS · T32 GM007205 · United States
Arthritis Research UK · United Kingdom
Medical Research Council · MR/K006584/1 · United Kingdom
NHLBI NIH HHS · UM1 HL098147 · United States
Wellcome Trust · United Kingdom
NHLBI NIH HHS · UM1 HL098123 · United States
Howard Hughes Medical Institute · United States
Department of Health · United Kingdom
External Links
PubMed source DOI: 10.1126/science.aac9396 PMC Full Text View journal details
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