title: De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Homsy
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: James S
authors.initials: JS
authors.lastname: Ware
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA.
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: DePalma
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: McKean
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Gorham
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Sheng Chih
authors.initials: SC
authors.lastname: Jin
authors.affiliation: Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
authors.affiliation: Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giardini
authors.affiliation: Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Porter
authors.affiliation: Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
authors.forename: Francesc
authors.initials: F
authors.lastname: López-Giráldez
authors.affiliation: Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Tikhonova
authors.affiliation: Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Romano-Adesman
authors.affiliation: 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.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Badri
authors.initials: B
authors.lastname: Vardarajan
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Lijiang
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.affiliation: Department of Cardiology, Children's Hospital Boston, Boston, MA, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Roberts
authors.affiliation: Division of Pediatric Cardiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russell
authors.affiliation: Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Seema
authors.initials: S
authors.lastname: Mital
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Jane W
authors.initials: JW
authors.lastname: Newburger
authors.affiliation: Department of Pediatric Cardiac Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: J William
authors.initials: JW
authors.lastname: Gaynor
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: Breitbart
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Iossifov
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ronemus
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, MD, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Kaltman
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: 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.
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckner
authors.affiliation: 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.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.affiliation: 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.affiliation: 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.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: 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.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: 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.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D001921:Brain / Q000002:abnormalities / Q000378:metabolism; D002648:Child; D000013:Congenital Abnormalities / Q000235:genetics; D059472:Exome / Q000235:genetics; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D011379:Prognosis; D012326:RNA Splicing / Q000235:genetics; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins