ArticleAmerican journal of human genetics2014
Rare variants in NR2F2 cause congenital heart defects in humans.
Erratum issuedOpen access · hybridAbstract read
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Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 99 papers.
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99citing papers in PubMed
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Who cites it
99 citing papers in PubMed, 185 citations in OpenAlex.
- A cell atlas of the developing human outflow tract of the heart and its adult aortic valve derivatives.eLife · 2026Article
- Nr2f1a and Isl1 repress acquisition of epicardial identity in venous atrial cardiomyocytes.Development (Cambridge, England) · 2026Article
- DNA Methylation and Fetal Programming of Cardiovascular Disease: From Congenital Heart Diseases to Adult Cardiovascular Dysfunction.Reviews in cardiovascular medicine · 2026Review
- Cranial neural crest shortage leads to extensive craniofacial anomalies in mice mutant for the NR2F1/2 nuclear receptors.Developmental biology · 2026Article
- Reduced TBX5 dosage undermines developmental control of atrial cardiomyocyte identity in a model of human atrial disease.Development (Cambridge, England) · 2026Article
- Identifying novel Japanese heart failure variants via endothelialBioinformatics advances · 2026Article
- Review
- In Vivo Models of Cardiovascular Disease:Biomedicines · 2025Review
- Inhibition of NR2F2 suppresses invasion ability and modulates EMT marker in head and neck squamous cell carcinoma.Discover oncology · 2025Article
- Role of COUP‑TFII in cardiovascular diseases and colorectal cancer: Insights into the molecular mechanisms and clinical relevance (Review).Molecular medicine reports · 2025Review
- A novel HPβCD-Cu(DDC)Scientific reports · 2025Article
- A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish.PLoS genetics · 2024Article
- Article
- Zebrafish Congenital Heart Disease Models: Opportunities and Challenges.International journal of molecular sciences · 2024Review
- A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish.bioRxiv : the preprint server for biology · 2024Article
- COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors.Cell & bioscience · 2024Article
- Testicular differentiation in 46,XX DSD: an overview of genetic causes.Frontiers in endocrinology · 2024Review
- Human Genetics of Ventricular Septal Defect.Advances in experimental medicine and biology · 2024Article
- Human Genetics of Atrioventricular Septal Defect.Advances in experimental medicine and biology · 2024Review
- Low-dose exercise protects the heart against established myocardial infarction via IGF-1-upregulated CTRP9 in male mice.MedComm · 2023Article
39 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issuedRare Variants in NR2F2 Cause Congenital Heart Defects in Humans.2016 · Low, Jacoba [corrected to Louw, Jacoba]
- Erratum issued
Authors and funding
41 authors at 19 institutions in 7 countries.
Saeed Al TurkiWellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Pathology, King Abdulaziz Medical City, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
Ashok K ManickarajDivision of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
Catherine L MercerHuman Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Sebastian S GeretyWellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Marc-Phillip HitzWellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Sarah LindsayWellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Lisa C A D'AlessandroDivision of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
G Jawahar SwaminathanWellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Jamie BenthamDepartment of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02459, USA.
Anne-Karin ArndtCardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
Jacoba Louw
Jacoba LowCentre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Pediatric Cardiology Unit, University Hospital Leuven, 3000 Leuven, Belgium.
Jeroen BreckpotCentre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Marc GewilligPediatric Cardiology Unit, University Hospital Leuven, 3000 Leuven, Belgium.
Bernard ThienpontCentre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Hashim Abdul-KhaliqDepartment of Pediatric Cardiology, Saarland University Hospital, 66421 Homburg, Germany; Competence Network for Congenital Heart Defects.
Christine HarnackExperimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max-Delbruck-Center for Molecular Medicine, 13125 Berlin, Germany.
Kirstin HoffDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Institute of Human Genetics, Christian-Albrechts University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
Hans-Heiner KramerDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Competence Network for Congenital Heart Defects.
Stephan SchubertCompetence Network for Congenital Heart Defects; Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, 13353 Berlin, Germany.
Reiner SiebertInstitute of Human Genetics, Christian-Albrechts University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
Okan TokaCompetence Network for Congenital Heart Defects; Department of Pediatric Cardiology, Children's Hospital, Friedrich-Alexander University, 91054 Erlangen, Germany.
Catherine CosgroveRadcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Hugh WatkinsRadcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Anneke M LucassenHuman Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Ita M O'KellyHuman Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Anthony P SalmonHuman Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Frances A Bu'lockEast Midlands Congenital Heart Centre, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK.
Javier Granados-RiveronSchool of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Kerry SetchfieldSchool of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Chris ThornboroughEast Midlands Congenital Heart Centre, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK.
J David BrookSchool of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Barbara MulderHeart Center, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
Sabine KlaassenCompetence Network for Congenital Heart Defects; Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max-Delbruck-Center for Molecular Medicine, 13125 Berlin, Germany; Department of Pediatric Cardiology, Charité University Medicine Berlin,13353 Berlin, Germany.
Shoumo BhattacharyaRadcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Koen DevriendtCentre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
David F FitzpatrickMRC Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
UK10K Consortium
David I WilsonHuman Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Seema MitalDivision of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: seema.mital@sickkids.ca.
Matthew E HurlesWellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: meh@sanger.ac.uk.
Wellcome Sanger Institute · GBKU Leuven · BEAdult Congenital Heart Association · USUniversity of Nottingham · GBUniversity of Southampton · GBHospital for Sick Children · CASouthampton General Hospital · GBUniversity Hospital Schleswig-Holstein · DEUniversity Hospitals of Leicester NHS Trust · GBUniversity of Oxford · GBAcademic Medical Center · NLBoston Children's Hospital · USCentre for Human Genetics · GBCharité - Universitätsmedizin Berlin · DEDeutsches Herzzentrum der Charité · DEFriedrich-Alexander-Universität Erlangen-Nürnberg · DEKiel University · DEMRC Institute of Genetics and Molecular Medicine · GBUniversity of Toronto · CA
Funding
Comprehensive Sequencing and Analysis of Variation in NHLBI CohortsUC2HL102925 · NHLBI · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, GABRIEL, STACEY · 2010 to 2010
$14.7MNorthwest Genomics CenterUC2HL102926 · NHLBI · UNIVERSITY OF WASHINGTON · PI GREEN, PHILIP P, NICKERSON, DEBORAH A · 2010 to 2010
$14.0MNorthwest Genomics CenterRC2HL102926 · NHLBI · UNIVERSITY OF WASHINGTON · PI GREEN, PHILIP P, NICKERSON, DEBORAH A · 2009 to 2009
$11.0MComprehensive Sequencing and Analysis of Variation in NHLBI CohortsRC2HL102925 · NHLBI · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, GABRIEL, STACEY · 2009 to 2009
$10.2MARRA - NHLBI Lung Cohorts Sequencing ProjectRC2HL102923 · NHLBI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, BARNES, KATHLEEN C · 2009 to 2009
$2.6MARRA - NHLBI Lung Cohorts Sequencing ProjectUC2HL102923 · NHLBI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, BARNES, KATHLEEN C · 2010 to 2010
$2.6MWHI Sequencing Project (WHISP)UC2HL102924 · NHLBI · OHIO STATE UNIVERSITY · PI CARLSON, CHRISTOPHER S, JACKSON, REBECCA D · 2010 to 2010
$2.4MWHI Sequencing Project (WHISP)RC2HL102924 · NHLBI · OHIO STATE UNIVERSITY · PI CARLSON, CHRISTOPHER S, JACKSON, REBECCA D · 2009 to 2009
$2.1MHuman Exome Sequencing in Six Well-Phenotyped NHLBI CohortsUC2HL103010 · NHLBI · UNIVERSITY OF VIRGINIA · PI RICH, STEPHEN S. · 2010 to 2010
$1.5MHuman Exome Sequencing in Six Well-Phenotyped NHLBI CohortsRC2HL103010 · NHLBI · UNIVERSITY OF VIRGINIA · PI RICH, STEPHEN S. · 2009 to 2009
$817kBritish Heart Foundation PG/07/045/22690British Heart Foundation RG/07/010/23676British Heart Foundation RG/10/17/28553British Heart Foundation RG/13/10/30376Medical Research Council MC_PC_U127561093Medical Research Council MC_U127561093NHLBI NIH HHS RC2 HL102923NHLBI NIH HHS RC2 HL102924NHLBI NIH HHS RC2 HL102925NHLBI NIH HHS RC2 HL102926NHLBI NIH HHS RC2 HL103010NHLBI NIH HHS UC2 HL102923NHLBI NIH HHS UC2 HL102924NHLBI NIH HHS UC2 HL102925NHLBI NIH HHS UC2 HL102926NHLBI NIH HHS UC2 HL103010Wellcome Trust 090532Wellcome Trust 100140Wellcome Trust WT098051
Abstract
Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters.
Indexed as
AnimalsBinding SitesCell LineCOUP Transcription Factor IIExomeFemaleHeart Defects, CongenitalHumansMaleMiceMutation, MissensePedigreeProspective StudiesTranscription, GeneticCOUP Transcription Factor IINR2F2 protein, human
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