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

Jason Homsy; Samir Zaidi; Yufeng Shen; James S Ware; Kaitlin E Samocha; Konrad J Karczewski; Steven R DePalma; David McKean; Hiroko Wakimoto; Josh Gorham; Sheng Chih Jin; John Deanfield; Alessandro Giardini; George A Porter Jr; Richard Kim; Kaya Bilguvar; Francesc López-Giráldez; Irina Tikhonova; Shrikant Mane; Angela Romano-Adesman; Hongjian Qi; Badri Vardarajan; Lijiang Ma; Mark Daly; Amy E Roberts; Mark W Russell; Seema Mital; Jane W Newburger; J William Gaynor; Roger E Breitbart; Ivan Iossifov; Michael Ronemus; Stephan J Sanders; Jonathan R Kaltman; Jonathan G Seidman; Martina Brueckner; Bruce D Gelb; Elizabeth Goldmuntz; Richard P Lifton; Christine E Seidman; Wendy K Chung

doi:10.1126/science.aac9396

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

Science. 2015 Dec 4;350(6265):1262-6. doi: 10.1126/science.aac9396.

Authors

Jason Homsy¹, Samir Zaidi², Yufeng Shen³, James S Ware⁴, Kaitlin E Samocha⁵, Konrad J Karczewski⁵, Steven R DePalma⁶, David McKean⁷, Hiroko Wakimoto⁷, Josh Gorham⁷, Sheng Chih Jin², John Deanfield⁸, Alessandro Giardini⁸, George A Porter Jr⁹, Richard Kim¹⁰, Kaya Bilguvar¹¹, Francesc López-Giráldez¹², Irina Tikhonova¹², Shrikant Mane¹², Angela Romano-Adesman¹³, Hongjian Qi¹⁴, Badri Vardarajan¹⁵, Lijiang Ma¹⁶, Mark Daly⁵, Amy E Roberts¹⁷, Mark W Russell¹⁸, Seema Mital¹⁹, Jane W Newburger²⁰, J William Gaynor²¹, Roger E Breitbart²⁰, Ivan Iossifov²², Michael Ronemus²², Stephan J Sanders²³, Jonathan R Kaltman²⁴, Jonathan G Seidman⁷, Martina Brueckner²⁵, Bruce D Gelb²⁶, Elizabeth Goldmuntz²⁷, Richard P Lifton²⁸, Christine E Seidman²⁹, Wendy K Chung³⁰

Affiliations

¹ Department of Genetics, Harvard Medical School, Boston, MA, USA. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
² Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
³ Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
⁴ 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.
⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA.
⁶ Department of Genetics, Harvard Medical School, Boston, MA, USA. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA.
⁷ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁸ Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK.
⁹ Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, NY, USA.
¹⁰ Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
¹¹ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
¹² Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
¹³ Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA.
¹⁴ 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.
¹⁵ Department of Neurology, Columbia University Medical Center, New York, NY, USA.
¹⁶ Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
¹⁷ Department of Cardiology, Children's Hospital Boston, Boston, MA, USA.
¹⁸ Division of Pediatric Cardiology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
²⁰ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
²¹ Department of Pediatric Cardiac Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²² Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
²³ Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
²⁴ Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, MD, USA.
²⁵ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu.
²⁶ Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu.
²⁷ 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. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu.
²⁸ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu.
²⁹ 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. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu.
³⁰ Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain / abnormalities
Brain / metabolism
Child
Congenital Abnormalities / genetics
Exome / genetics
Heart Defects, Congenital / diagnosis*
Heart Defects, Congenital / 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

Substances

RBFOX2 protein, human
RNA Splicing Factors
RNA, Messenger
RNA-Binding Proteins
Repressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding