Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

被引：24

作者：

Audain, Enrique ^{[1
,2
]}

Wilsdon, Anna ^{[3
]}

Breckpot, Jeroen ^{[4
]}

Izarzugaza, Jose M. G. ^{[5
]}

Fitzgerald, Tomas W. ^{[6
]}

Kahlert, Anne-Karin ^{[1
,2
,7
]}

Sifrim, Alejandro ^{[8
,9
]}

Wunnemann, Florian ^{[10
]}

Perez-Riverol, Yasset ^{[11
]}

Abdul-Khaliq, Hashim ^{[12
]}

Bak, Mads ^{[13
,14
]}

Bassett, Anne S. ^{[15
,16
,17
]}

Benson, Woodrow D. ^{[18
]}

Berger, Felix ^{[19
]}

Daehnert, Ingo ^{[20
]}

Devriendt, Koenraad ^{[4
]}

Dittrich, Sven ^{[21
]}

Daubeney, Piers E. F. ^{[22
]}

Garg, Vidu ^{[23
,24
,25
,26
]}

Hackmann, Karl ^{[7
]}

Hoff, Kirstin ^{[1
,2
]}

Hofmann, Philipp ^{[1
,2
]}

Dombrowsky, Gregor ^{[1
,2
]}

Pickardt, Thomas ^{[27
]}

Bauer, Ulrike ^{[27
]}

Keavney, Bernard D. ^{[28
,29
]}

Klaassen, Sabine ^{[30
,31
,32
,33
,34
,35
]}

Kramer, Hans-Heiner ^{[1
,2
]}

Marshall, Christian R. ^{[36
,37
]}

Milewicz, Dianna M. ^{[38
]}

Lemaire, Scott ^{[39
]}

Coselli, Joseph S. ^{[40
]}

Mitchell, Michael E. ^{[40
]}

Tomita-Mitchell, Aoy ^{[40
]}

Prakash, Siddharth K. ^{[38
]}

Stamm, Karl ^{[40
]}

Stewart, Alexandre F. R. ^{[41
]}

Silversides, Candice K. ^{[15
,16
]}

Siebert, Reiner ^{[42
,43
]}

Stiller, Brigitte ^{[44
]}

Rosenfeld, Jill A. ^{[18
]}

Vater, Inga ^{[43
]}

Postma, Alex V. ^{[45
,46
]}

Caliebe, Almuth ^{[43
]}

Brook, J. David ^{[3
]}

Andelfinger, Gregor ^{[47
]}

Hurles, Matthew E. ^{[48
]}

Thienpont, Bernard ^{[4
,49
]}

Larsen, Lars Allan ^{[13
]}

Hitz, Marc-Phillip ^{[1
,2
,43
,48
]}

机构：

[1] Univ Hosp Schleswig Holstein, Dept Congenital Heart Dis & Pediat Cardiol, Kiel, Germany

[2] German Ctr Cardiovasc Res DZHK, Kiel, Germany

[3] Univ Nottingham, Sch Life Sci, Univ Pk, Nottingham, England

[4] Katholieke Univ Leuven, Ctr Human Genet, Leuven, Belgium

[5] Tech Univ Denmark, Dept Hlth Technol, Lyngby, Denmark

[6] Wellcome Genome Campus, European Bioinformat Inst EMBL EBI, Cambridge, England

[7] Tech Univ Dresden, Inst Clin Genet, Fac Med Carl Gustav Carus, Dresden, Germany

[8] Katholieke Univ Leuven, Univ Leuven, Dept Human Genet, Leuven, Belgium

[9] Wellcome Trust Sanger Inst, Sanger Inst, EBI Single Cell Genom Ctr, Hinxton, England

[10] Univ Montreal, Montreal Heart Inst, Quebec City, PQ, Canada

[11] Wellcome Trust Genome Campus, European Bioinformat Inst EMBL EBI, European Mol Biol Lab, Cambridge, England

[12] Univ Hosp Saarland, Clin Pediat Cardiol, Homburg, Saar, Germany

[13] Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark

[14] Copenhagen Univ Hosp, Dept Clin Genet, Rigshospitalet, Copenhagen, Denmark

[15] Univ Hlth Network, Toronto Congenital Cardiac Ctr Adults, Toronto, ON, Canada

[16] Univ Hlth Network, Div Cardiol, Dept Med, Toronto, ON, Canada

[17] Univ Toronto, Dept Psychiat, Toronto, ON, Canada

[18] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA

[19] German Heart Ctr Berlin, Dept Congenital Heart Dis Pediat Cardiol, Berlin, Germany

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

[21] Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Hosp Erlangen, Dept Pediat Cardiol, Erlangen, Germany

[22] Royal Brompton Hosp, Div Paediat Cardiol, London, England

[23] Nationwide Childrens Hosp, Heart Ctr, Columbus, OH USA

[24] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA

[25] Nationwide Childrens Hosp, Ctr Cardiovasc Res, Columbus, OH USA

[26] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA

[27] Competence Network Congenital Heart Defects, Berlin, Germany

[28] Univ Manchester, Sch Med Sci, Div Cardiovasc Sci, Fac Biol Med & Hlth, Manchester, Lancs, England

[29] Univ Manchester, Sch Biol Sci, Div Evolut & Genom Sci, Fac Biol Med & Hlth, Manchester, Lancs, England

[30] Joint Cooperat Charite Med Fac & Max Delbruck Ctr, Expt & Clin Res Ctr ECRC, Berlin, Germany

[31] Charite Univ Med Berlin, Berlin, Germany

[32] Free Univ Berlin, Berlin, Germany

[33] Humboldt Univ, Berlin, Germany

[34] Berlin Inst Hlth, Dept Pediat Cardiol, Berlin, Germany

[35] DZHK German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany

[36] Hosp Sick Children, Ctr Appl Genom, Toronto, ON, Canada

[37] Hosp Sick Children, Dept Paediat Lab Med, Genome Diagnost, Toronto, ON, Canada

[38] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, McGovern Med Sch, Houston, TX 77030 USA

[39] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA

[40] Med Coll Wisconsin, Dept Surg, Div Cardiothorac Surg, 8700 W Wisconsin Ave, Milwaukee, WI 53226 USA

[41] Univ Ottawa Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada

[42] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany

[43] Univ Med Ctr Schleswig Holstein UKSH, Dept Human Genet, Kiel, Germany

[44] Univ Heart Ctr Freiburg Bad Krozingen, Dept Congenital Heart Dis & Pediat Cardiol, Freiburg, Germany

[45] Univ Amsterdam, Amsterdam UMC, Dept Med Biol, Amsterdam, Netherlands

[46] Univ Amsterdam, Amsterdam UMC, Dept Clin Genet, Amsterdam, Netherlands

[47] Univ Montreal, Ctr Hosp Univ St Justine, Res Ctr, Cardiovasc Genet,Dept Pediat, Montreal, PQ, Canada

[48] Wellcome Genome Campus, Wellcome Sanger Inst, Cambridge, England

[49] Katholieke Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium

来源：

PLOS GENETICS | 2021年 / 17卷 / 07期

关键词：

DE-NOVO MUTATIONS; NALCN CAUSE; DEFECTS; RISK; PREVALENCE; HYPOTONIA; GENETICS; FEATURES; NETWORK;

D O I：

10.1371/journal.pgen.1009679

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. Author summary Congenital heart disease (CHD) is the most common congenital anomaly and represents a major global health burden. Multiple studies have identified a key genetic component contributing to the aetiology of CHD. However, despite the advances in the field of CHD within the last three decades, the genetic causes underlying CHD are still not fully understood. Herein we have assembled a large patient CHD cohort and performed a data-driven meta-analysis of genomic variants in CHD. This analysis has allowed us to strengthen the disease association of known CHD genes, as well as identifying novel haploinsufficient CHD candidate genes.

引用

页数：24

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