Rare variants in NR2F2 cause congenital heart defects in humans.
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.
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Pathology, King Abdulaziz Medical City, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
Saeed
S
Al Turki
Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
Ashok K
AK
Manickaraj
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Catherine L
CL
Mercer
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Sebastian S
SS
Gerety
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Marc-Phillip
MP
Hitz
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Sarah
S
Lindsay
Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
Lisa C A
LC
D'Alessandro
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
G Jawahar
GJ
Swaminathan
Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02459, USA.
Jamie
J
Bentham
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.
Anne-Karin
AK
Arndt
Jacoba
J
Louw
Centre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Pediatric Cardiology Unit, University Hospital Leuven, 3000 Leuven, Belgium.
Jacoba
J
Low
Centre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Jeroen
J
Breckpot
Pediatric Cardiology Unit, University Hospital Leuven, 3000 Leuven, Belgium.
Marc
M
Gewillig
Centre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Bernard
B
Thienpont
Department of Pediatric Cardiology, Saarland University Hospital, 66421 Homburg, Germany; Competence Network for Congenital Heart Defects.
Hashim
H
Abdul-Khaliq
Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max-Delbruck-Center for Molecular Medicine, 13125 Berlin, Germany.
Christine
C
Harnack
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.
Kirstin
K
Hoff
Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Competence Network for Congenital Heart Defects.
Hans-Heiner
HH
Kramer
Competence Network for Congenital Heart Defects; Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, 13353 Berlin, Germany.
Stephan
S
Schubert
Institute of Human Genetics, Christian-Albrechts University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
Reiner
R
Siebert
Competence Network for Congenital Heart Defects; Department of Pediatric Cardiology, Children's Hospital, Friedrich-Alexander University, 91054 Erlangen, Germany.
Okan
O
Toka
Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Catherine
C
Cosgrove
Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Hugh
H
Watkins
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Anneke M
AM
Lucassen
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Ita M
IM
O'Kelly
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Anthony P
AP
Salmon
East Midlands Congenital Heart Centre, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK.
Frances A
FA
Bu'lock
School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Javier
J
Granados-Riveron
School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
Kerry
K
Setchfield
East Midlands Congenital Heart Centre, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK.
Chris
C
Thornborough
School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
J David
JD
Brook
Heart Center, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
Barbara
B
Mulder
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.
Sabine
S
Klaassen
Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Shoumo
S
Bhattacharya
Centre for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Koen
K
Devriendt
MRC Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
David F
DF
Fitzpatrick
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
David I
DI
Wilson
Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: seema.mital@sickkids.ca.
Seema
S
Mital
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: meh@sanger.ac.uk.
Matthew E
ME
Hurles
D000818:Animals; D001665:Binding Sites; D051837:COUP Transcription Factor II / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D059472:Exome; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010375:Pedigree; D011446:Prospective Studies; D014158:Transcription, Genetic
D051837:COUP Transcription Factor II; C095569:NR2F2 protein, human