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Rare variants in NR2F2 cause congenital heart defects in humans

Rare variants in NR2F2 cause congenital heart defects in humans
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.
0002-9297
574-585
Al Turki, Saeed
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Gewillig, Marc
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Lucassen, Anneke M.
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Bhattacharya, Shoumo
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FitzPatrick, David F.
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UK10K Consortium
Al Turki, Saeed
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Manickaraj, Ashok K.
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Mercer, Catherine L.
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Lucassen, Anneke M.
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O’Kelly, Ita M.
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Salmon, Anthony P.
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Bu’Lock, Frances A.
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Granados-Riveron, Javier
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Mulder, Barbara
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Klaassen, Sabine
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Bhattacharya, Shoumo
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Devriendt, Koen
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FitzPatrick, David F.
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Wilson, David I.
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Mital, Seema
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Hurles, Matthew E.
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UK10K Consortium (2014) Rare variants in NR2F2 cause congenital heart defects in humans. The American Journal of Human Genetics, 94 (4), 574-585. (doi:10.1016/j.ajhg.2014.03.007). (PMID:24702954)

Record type: Article

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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Accepted/In Press date: 12 March 2014
e-pub ahead of print date: 3 April 2014
Published date: 3 April 2014
Additional Information: This article has a correction. Please see: 10.1016/j.ajhg.2014.06.013 10.1016/j.ajhg.2016.02.016
Organisations: Cancer Sciences, Human Development & Health

Identifiers

Local EPrints ID: 364166
URI: http://eprints.soton.ac.uk/id/eprint/364166
ISSN: 0002-9297
PURE UUID: f3ae30a5-b27e-48bb-b786-b5fdb74f7bdd
ORCID for Anneke M. Lucassen: ORCID iD orcid.org/0000-0003-3324-4338

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Date deposited: 07 Apr 2014 16:13
Last modified: 15 Mar 2024 03:11

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Contributors

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

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