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Circ Res. 2014 Oct 24;115(10):884-896. doi: 10.1161/CIRCRESAHA.115.304458. Epub 2014 Sep 9.

Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.

Author information

1
The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
2
Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
3
Genetics, Harvard Medical School, Boston, MA 02115, USA.
4
Mindich Child Health and Development Institute, Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Psychiatric Genomics in the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
9
Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
10
Genetics, Yale University, New Haven, CT 06520, USA.
11
Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
12
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
13
Cardiovascular Sciences, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA.
14
Genetics and Development (in Medicine), Columbia University Medical Center, New York, NY 10032, USA.
15
Pediatrics, Yale University, New Haven, CT 06520, USA.
16
Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
17
Medicine, Yale University, New Haven, CT 06520, USA.
18
Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
#
Contributed equally

Abstract

RATIONALE:

Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.

OBJECTIVE:

To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.

METHODS AND RESULTS:

We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.

CONCLUSIONS:

We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.

KEYWORDS:

DNA copy number variations; genomics; microarray analysis; polymorphism, single nucleotide

PMID:
25205790
PMCID:
PMC4209190
DOI:
10.1161/CIRCRESAHA.115.304458
[Indexed for MEDLINE]
Free PMC Article

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