2. Academic Validation
  3. Rare variants in NR2F2 cause congenital heart defects in humans

Rare variants in NR2F2 cause congenital heart defects in humans

  • Am J Hum Genet. 2014 Apr 3;94(4):574-85. doi: 10.1016/j.ajhg.2014.03.007.
Saeed Al Turki 1,  Ashok K Manickaraj 2,  Catherine L Mercer 3,  Sebastian S Gerety 4,  Marc-Phillip Hitz 4,  Sarah Lindsay 4,  Lisa C A D'Alessandro 2,  G Jawahar Swaminathan 4,  Jamie Bentham 5,  Anne-Karin Arndt 6,  Jacoba Louw,  Jacoba Low 7,  Jeroen Breckpot 8,  Marc Gewillig 9,  Bernard Thienpont 8,  Hashim Abdul-Khaliq 10,  Christine Harnack 11,  Kirstin Hoff 12,  Hans-Heiner Kramer 13,  Stephan Schubert 14,  Reiner Siebert 15,  Okan Toka 16,  Catherine Cosgrove 17,  Hugh Watkins 17,  Anneke M Lucassen 3,  Ita M O'Kelly 3,  Anthony P Salmon 3,  Frances A Bu'lock 18,  Javier Granados-Riveron 19,  Kerry Setchfield 19,  Chris Thornborough 18,  J David Brook 19,  Barbara Mulder 20,  Sabine Klaassen 21,  Shoumo Bhattacharya 17,  Koen Devriendt 8,  David F Fitzpatrick 22,  UK10K Consortium,  David I Wilson 3,  Seema Mital 23,  Matthew E Hurles 24
Affiliations

Affiliations

  • 1 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Pathology, King Abdulaziz Medical City, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
  • 2 Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 3 Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
  • 4 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • 5 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02459, USA.
  • 6 Cardiovascular 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.
  • 7 Centre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Pediatric Cardiology Unit, University Hospital Leuven, 3000 Leuven, Belgium.
  • 8 Centre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
  • 9 Pediatric Cardiology Unit, University Hospital Leuven, 3000 Leuven, Belgium.
  • 10 Department of Pediatric Cardiology, Saarland University Hospital, 66421 Homburg, Germany; Competence Network for Congenital Heart Defects.
  • 11 Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max-Delbruck-Center for Molecular Medicine, 13125 Berlin, Germany.
  • 12 Department 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.
  • 13 Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Competence Network for Congenital Heart Defects.
  • 14 Competence Network for Congenital Heart Defects; Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, 13353 Berlin, Germany.
  • 15 Institute of Human Genetics, Christian-Albrechts University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
  • 16 Competence Network for Congenital Heart Defects; Department of Pediatric Cardiology, Children's Hospital, Friedrich-Alexander University, 91054 Erlangen, Germany.
  • 17 Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 18 East Midlands Congenital Heart Centre, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK.
  • 19 School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
  • 20 Heart Center, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
  • 21 Competence 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.
  • 22 MRC Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • 23 Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: seema.mital@sickkids.ca.
  • 24 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: meh@sanger.ac.uk.
PMID: 24702954 DOI: 10.1016/j.ajhg.2014.03.007
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.

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