Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

被引：309

作者：

Sifrim, Alejandro ^{[1
]}

Hitz, Marc-Phillip ^{[1
,2
,3
]}

Wilsdon, Anna ^{[4
]}

Breckpot, Jeroen ^{[5
]}

Al Turki, Saeed H. ^{[1
,6
,7
]}

Thienpont, Bernard ^{[8
,9
]}

McRae, Jeremy ^{[1
]}

Fitzgerald, Tomas W. ^{[1
]}

Singh, Tarjinder ^{[1
]}

Swaminathan, Ganesh Jawahar ^{[1
]}

Prigmore, Elena ^{[1
]}

Rajan, Diana ^{[1
]}

Abdul-Khaliq, Hashim ^{[10
,11
]}

Banka, Siddharth ^{[12
,13
]}

Bauer, Ulrike M. M. ^{[11
]}

Bentham, Jamie ^{[14
]}

Berger, Felix ^{[3
,11
,15
]}

Bhattacharya, Shoumo ^{[16
]}

Bu'Lock, Frances ^{[17
]}

Canham, Natalie ^{[18
]}

Colgiu, Irina-Gabriela ^{[1
]}

Cosgrove, Catherine ^{[16
]}

Cox, Helen ^{[19
]}

Daehnert, Ingo ^{[11
,20
]}

Daly, Allan ^{[1
]}

Danesh, John ^{[1
,21
,22
]}

Fryer, Alan ^{[23
]}

Gewillig, Marc ^{[24
]}

Hobson, Emma ^{[25
]}

Hoff, Kirstin ^{[2
,3
]}

Homfray, Tessa ^{[26
]}

Kahlert, Anne-Karin ^{[2
,3
,27
]}

Ketley, Ami ^{[4
]}

Kramer, Hans-Heiner ^{[2
,3
,11
]}

Lachlan, Katherine ^{[28
,29
,30
]}

Lampe, Anne Katrin ^{[31
]}

Louw, Jacoba J. ^{[24
]}

Manickara, Ashok Kumar ^{[32
]}

Manase, Dorin ^{[32
]}

McCarthy, Karen P. ^{[33
,34
]}

Metcalfe, Kay ^{[13
]}

Moore, Carmel ^{[22
]}

Newbury-Ecob, Ruth ^{[35
]}

Omer, Seham Osman ^{[36
]}

Ouwehand, Willem H. ^{[1
,21
,37
,38
]}

Park, Soo-Mi ^{[39
]}

Parker, Michael J. ^{[40
]}

Pickardt, Thomas ^{[11
]}

Pollard, Martin O. ^{[1
]}

Robert, Leema

机构：

[1] Wellcorne Trust Sanger Inst, Cambridge, England

[2] Univ Klinikum Schleswig Holstein Kiel, Dept Congenital Heart Dis & Pediat Cardiol, Kiel, Germany

[3] German Ctr Cardiovasc Res DZHK, Berlin, Germany

[4] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham, England

[5] Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium

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

[7] Harvard Med Sch, Genet training Pograrn, Boston, MA USA

[8] VIB, Vesalius Res Ctr, Leuven, Belgium

[9] Katholieke Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium

[10] Univ Saarland, Dept Pediat Cardiol, Homburg, Germany

[11] DZHK, Natl Register Congenital Heart Detects, Competence Network Congenital Heart Defects, Berlin, Germany

[12] Univ Manchester, Fac Med & Human Sci, Inst Human Dev, Manchester Ctr Genorn Med, Manchester, Lancs, England

[13] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, St Marys Hosp, Manchester Ctr Genom Med, Manchester, Lancs, England

[14] Yorkshire Heart Ctr, Dept Paediat Cardiol, Leeds, W Yorkshire, England

[15] Charite Univ Med Berlin, German Heart Inst Berlin, Dept Congenital Heart Dis & Pediat Cardiol, Berlin, Germany

[16] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[17] Glenfield Hosp, East Midlands Congenital Heart Ctr, Leicester, Leics, England

[18] London North West Healthcare NHS Trust, North West Thames Reg Genet Ctr, Harrow, Middx, England

[19] Birmingham Womens Hosp, Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England

[20] Univ Leipzig, Heart Ctr, Dept Pediat Cardiol, Leipzig, Germany

[21] Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth &, Cambridge, England

[22] Univ Cambridge, Dept Publ Hlth & Primary Care, INEERVAL Coordinating Ctr, Cambridge, England

[23] Liverpool Womens NHS Fdn Trust, Dept Clin Genet, Liverpool, Merseyside, England

[24] Univ Hosp, Dept Pediat Cardiol, Leuven, Belgium

[25] Chapel Allegan Hosp, Dept Clin Genet, Leeds Teaching Hosp NHS Trust, Yorkshire Reg Gener Serv, Leeds, W Yorkshire, England

[26] Univ London, St Georges Healthcare NHS Trust, South West Thames Reg Genet Ctr, London, England

[27] Carl Gustav Carus Fac Med, Inst Clin Genet, Dresden, Germany

[28] Princess Anne Hosp, Southampton Univ Hosp, Wessex Clin Genet Serv, Southampton, Hants, England

[29] Salisbury Dist lospital, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury, Wilts, England

[30] Univ Southampton, Fac Med, Southampton, Hants, England

[31] Western Gen Hosp, IGMM North, South East Scotland Clin Genet Serv, Edinburgh, Midlothian, Scotland

[32] Hosp Sick Children, Toronto, ON, Canada

[33] Imperial Coll, Royal Bromplon Hosp, Cardiac Morphol Unit, London, England

[34] Imperial Coll, Natl Heart & Lung Inst, London, England

[35] St Michaels Hosp, Dept Clin Genet, Bristol, Avon, England

[36] Minist Natl Guard Hlth Affairs, King Abdulaziz Med City, King Abdulaziz Cardiac Ctr, Div Pediat Cardiol, Riyadh, Saudi Arabia

[37] Univ Cambridge, Dept Haematol, Cambridge, England

[38] NHS Blood & Transplant, Cambridge, England

[39] Cambridge Univ Hosp NHS Fdn Trust, East Anglian Med Genet Serv, Cambridge Biomed Campus, Cambridge, England

[40] Sheffield Childrens Hosp NHS Fdn Trust, Western Bank, Sheffield, S Yorkshire, England

[41] Guys Hosp, Guys & St Thomas NHS Fdn Trust, South East Thames Reg Genet Ctr, London, England

[42] John Radcliffe Hosp, NHS Blood & Transplant, Oxford, England

[43] Univ Oxford, John Radcliffe Hosp, Radcliffe Dept Med, Oxford, England

[44] Univ Freiburg, Ctr Heart, Dept Congenital Heart Defects & Pediat Cardiol, Freiburg, Germany

[45] Univ Erlangen Nurnberg, Dept Pediat Cardiol, Erlangen, Germany

[46] Newcastle UponTyne Hosp NHS Fdn Trust, Inst Human Genet, Int Ctr Life, Northern Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England

[47] Royal Bromplon Hosp, Div Paediat Cardiol, London, England

[48] Imperial Coll, Paediat Cardiol, London, England

[49] Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England

[50] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England

来源：

NATURE GENETICS | 2016年 / 48卷 / 09期

基金：

英国惠康基金; 加拿大健康研究院; 英国医学研究理事会;

关键词：

DE-NOVO MUTATIONS; DISEASE; RECURRENCE; DISCOVERY; FRAMEWORK; GENOTYPE;

D O I：

10.1038/ng.3627

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (similar to 2.7%)(3), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance(4,5). De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations(6,7). We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings(8). Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

引用

页码：1060 / +

页数：9

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