Rare variants in NR2F2 cause congenital heart defects in humans

UK10K Consortium, Saeed Al Turki, Ashok K Manickaraj, Catherine L Mercer, Sebastian S Gerety, Marc-Phillip Hitz, Sarah Lindsay, Lisa C A D'Alessandro, G Jawahar Swaminathan, Jamie Bentham, Anne-Karin Arndt, Jacoba Low, Jeroen Breckpot, Marc Gewillig, Bernard Thienpont, Hashim Abdul-Khaliq, Christine Harnack, Kirstin Hoff, Hans-Heiner Kramer, Stephan SchubertReiner Siebert, Okan Toka, Catherine Cosgrove, Hugh Watkins, Anneke M Lucassen, Ita M O'Kelly, Anthony P Salmon, Frances A Bu'lock, Javier Granados-Riveron, Kerry Setchfield, Chris Thornborough, J David Brook, Barbara Mulder, Sabine Klaassen, Shoumo Bhattacharya, Koen Devriendt, David F Fitzpatrick, David I Wilson, Seema Mital, Matthew E Hurles

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)574-85
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 3 Apr 2014


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