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Rare variants in NR2F2 cause congenital heart defects in humans

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Item Type:Article
Title:Rare variants in NR2F2 cause congenital heart defects in humans
Creators Name:Al Turki, S. and Manickaraj, A.K. and Mercer, C.L. and Gerety, S.S. and Hitz, M.P. and Lindsay, S. and D'Alessandro, L.C.A. and Swaminathan, G.J. and Bentham, J. and Arndt, A.K. and Low, J. and Breckpot, J. and Gewillig, M. and Thienpont, B. and Abdul-Khaliq, H. and Harnack, C. and Hoff, K. and Kramer, H.H. and Schubert, S. and Siebert, R. and Toka, O. and Cosgrove, C. and Watkins, H. and Lucassen, A.M. and O'Kelly, I.M. and Salmon, A.P. and Bu'Lock, F.A. and Granados-Riveron, J. and Setchfield, K. and Thornborough, C. and Brook, J.D. and Mulder, B. and Klaassen, S. and Bhattacharya, S. and Devriendt, K. and Fitzpatrick, D.F. and Wilson, D.I. and Mital, S. and Hurles, M.E.
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.
Keywords:Binding Sites, COUP Transcription Factor II, Cell Line, Exome, Congenital Heart Defects, Missense Mutation, Pedigree, Prospective Studies, Genetic Transcription, Animals, Mice
Source:American Journal of Human Genetics
Publisher:Cell Press / Elsevier
Page Range:574-585
Date:3 April 2014
Additional Information:Erratum in: Am J Hum Genet 94(1): 126.
Official Publication:https://doi.org/10.1016/j.ajhg.2014.03.007
PubMed:View item in PubMed

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