Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

被引：125

作者：

Al Turki, Saeed ^{[1
,2
]}

Manickaraj, Ashok K. ^{[3
]}

Mercer, Catherine L. ^{[4
]}

Gerety, Sebastian S. ^{[1
]}

Hitz, Marc-Phillip ^{[1
]}

Lindsay, Sarah ^{[1
]}

D'Alessandro, Lisa C. A. ^{[3
]}

Swaminathan, G. Jawahar ^{[1
]}

Bentham, Jamie ^{[5
]}

Arndt, Anne-Karin ^{[6
,7
,8
]}

Low, Jacoba ^{[9
,10
]}

Breckpot, Jeroen ^{[9
]}

Gewillig, Marc ^{[10
]}

Thienpont, Bernard ^{[9
]}

Abdul-Khaliq, Hashim ^{[11
,12
]}

Harnack, Christine ^{[13
,14
]}

Hoff, Kirstin ^{[8
,15
,16
]}

Kramer, Hans-Heiner ^{[8
,12
]}

Schubert, Stephan ^{[12
,17
]}

Siebert, Reiner ^{[15
,16
]}

Toka, Okan ^{[12
,18
]}

Cosgrove, Catherine ^{[19
,20
]}

Watkins, Hugh ^{[19
,20
]}

Lucassen, Anneke M. ^{[4
]}

O'Kelly, Ita M. ^{[4
]}

Salmon, Anthony P. ^{[4
]}

Bu'Lock, Frances A. ^{[21
]}

Granados-Riveron, Javier ^{[22
]}

Setchfield, Kerry ^{[22
]}

Thornborough, Chris ^{[21
]}

Brook, J. David ^{[22
]}

Mulder, Barbara ^{[23
]}

Klaassen, Sabine ^{[12
,13
,14
,24
]}

Bhattacharya, Shoumo ^{[19
,20
]}

Devriendt, Koen ^{[9
]}

FitzPatrick, David F. ^{[25
]}

Wilson, David I. ^{[4
]}

Mital, Seema ^{[3
]}

Hurles, Matthew E. ^{[1
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[2] King Abdul Aziz Med City, Dept Pathol, Riyadh 11426, Saudi Arabia

[3] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Cardiol, Toronto, ON M5G 1X8, Canada

[4] Univ Southampton, Southampton Gen Hosp, Fac Med, Human Dev & Hlth Acad Unit, Southampton SO16 6YD, Hants, England

[5] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Cardiol, Boston, MA 02459 USA

[6] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div, Boston, MA 02115 USA

[7] Harvard Stem Cell Inst, Boston, MA 02115 USA

[8] Univ Hosp Schleswig Holstein, Dept Congenital Heart Dis & Pediat Cardiol, D-24105 Kiel, Germany

[9] Katholieke Univ Leuven, Ctr Human Genet, B-3000 Louvain, Belgium

[10] Katholieke Univ Leuven Hosp, Pediat Cardiol Unit, B-3000 Louvain, Belgium

[11] Saarland Univ Hosp, Dept Pediat Cardiol, D-66421 Homburg, Germany

[12] Fac Med Charite, Competence Network Congenital Heart Defects, D-13125 Berlin, Germany

[13] Fac Med Charite, ECRC, D-13125 Berlin, Germany

[14] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany

[15] Univ Kiel, Inst Human Genet, D-24105 Kiel, Germany

[16] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany

[17] Deutsch Herzzentrum Berlin, Dept Congenital Heart Dis & Pediat Cardiol, D-13353 Berlin, Germany

[18] Univ Erlangen Nurnberg, Childrens Hosp, Dept Pediat Cardiol, D-91054 Erlangen, Germany

[19] Univ Oxford, Radcliffe Dept Med, Oxford OX3 7BN, England

[20] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[21] Univ Hosp Leicester NHS Trust, East Midlands Congenital Heart Ctr, Leicester LE3 9QP, Leics, England

[22] Univ Nottingham, Sch Life Sci, Nottingham NG7 2UH, England

[23] Univ Amsterdam, Acad Med Ctr, Ctr Heart, NL-1105 AZ Amsterdam, Netherlands

[24] Charite, Dept Pediat Cardiol, D-13353 Berlin, Germany

[25] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2014年 / 94卷 / 04期

基金：

英国惠康基金;

关键词：

COMPARATIVE GENOMIC HYBRIDIZATION; ATRIOVENTRICULAR SEPTAL-DEFECTS; DIAPHRAGMATIC-HERNIA; COUP-TFII; CURRENT KNOWLEDGE; GENE-EXPRESSION; DISEASE; MUTATIONS; ORPHAN; DIFFERENTIATION;

D O I：

10.1016/j.ajhg.2014.03.007

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Non-syndromic 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 x 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.

引用

页码：574 / 585

页数：12

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