Title: Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans
Authors: Al Turki, Saeed ×
Manickaraj, Ashok K
Mercer, Catherine L
Gerety, Sebastian S
Hitz, Marc-Phillip
Lindsay, Sarah
D'Alessandro, Lisa C A
Swaminathan, G Jawahar
Bentham, Jamie
Arndt, Anne-Karin
Louw, Jacoba
Breckpot, Jeroen
Gewillig, Marc
Thienpont, Bernard
Abdul-Khaliq, Hashim
Harnack, Christine
Hoff, Kirstin
Kramer, Hans-Heiner
Schubert, Stephan
Siebert, Reiner
Toka, Okan
Cosgrove, Catherine
Watkins, Hugh
Lucassen, Anneke M
O'Kelly, Ita M
Salmon, Anthony P
Bu'lock, Frances A
Granados-Riveron, Javier
Setchfield, Kerry
Thornborough, Chris
Brook, J David
Mulder, Barbara
Klaassen, Sabine
Bhattacharya, Shoumo
Devriendt, Koenraad
Fitzpatrick, David F
UK10K Consortium
Wilson, David I
Mital, Seema
Hurles, Matthew E #
Issue Date: Apr-2014
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:94 issue:4 pages:574-85
Article number: 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.
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Genetics of Human Development
× corresponding author
# (joint) last author

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