De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot

被引：336

作者：

Greenway, Steven C. ^{[1
]}

Pereira, Alexandre C. ^{[2
]}

Lin, Jennifer C. ^{[1
]}

DePalma, Steven R. ^{[1
]}

Israel, Samuel J. ^{[1
]}

Mesquita, Sonia M. ^{[2
]}

Ergul, Emel ^{[3
]}

Conta, Jessie H. ^{[3
]}

Korn, Joshua M. ^{[1
,4
,5
]}

McCarroll, Steven A. ^{[1
,4
,5
]}

Gorham, Joshua M. ^{[1
]}

Gabriel, Stacey ^{[4
,5
]}

Altshuler, David M. ^{[1
,4
,5
]}

Quintanilla-Dieck, Maria de Lourdes ^{[1
,6
]}

Artunduaga, Maria Alexandra ^{[1
,6
]}

Eavey, Roland D. ^{[6
]}

Plenge, Robert M. ^{[4
,5
,7
]}

Shadick, Nancy A. ^{[7
]}

Weinblatt, Michael E. ^{[7
]}

De Jager, Philip L. ^{[4
,5
,8
]}

Hafler, David A. ^{[4
,5
,8
]}

Breitbart, Roger E. ^{[3
]}

Seidman, Jonathan G. ^{[1
]}

Seidman, Christine E. ^{[1
,9
]}

机构：

[1] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[2] Univ Sao Paulo, Sch Med, Inst Heart, Lab Genet & Mol Cardiol, Sao Paulo, Brazil

[3] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA

[4] Broad Inst Harvard, Cambridge, MA USA

[5] MIT, Cambridge, MA 02139 USA

[6] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA

[7] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA

[8] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA

[9] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 08期

基金：

美国国家卫生研究院;

关键词：

CONGENITAL HEART-DISEASE; DEPENDENT PROBE AMPLIFICATION; MUTATIONS CAUSE NOONAN; HYPERTROPHIC CARDIOMYOPATHY; CHROMOSOME; 1Q21.1; ALAGILLE-SYNDROME; HUMAN GENOME; SCHIZOPHRENIA; DELETIONS; DUPLICATIONS;

D O I：

10.1038/ng.415

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5-15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.

引用

页码：931 / U98

页数：6

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