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Cited by 268Genomic variations and chromosomal abnormalitiesCongenital heart defects researchGenomics and Rare Diseases

Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

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Glessner, Joseph T., Bick, Alexander G., Ito, Kaoru, Homsy, Jason G., Rodriguez-Murillo, Laura, Fromer, Menachem, Mazaika, Erica, Vardarajan, Badri +22 more·2014·Circulation Research
DOI 10.1161/circresaha.115.304458PMC PMC4209190
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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.

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Authors
Glessner, J. T., Bick, A. G., Ito, K., Homsy, J. G., Rodriguez-Murillo, L., Fromer, M., Mazaika, E., Vardarajan, B., Italia, M., Leipzig, J., DePalma, S. R., Golhar, R., Sanders, S. J., Yamrom, B., Ronemus, M., Iossifov, I., Willsey, A. J., State, M. W., Kaltman, J. R., White, P. S., Shen, Y., Warburton, D., Brueckner, M., Seidman, C., Goldmuntz, E., Gelb, B. D., Lifton, R., Seidman, J., Hakonarson, H., & Chung, W. K.
Affiliations
  • National Institutes of Health (US)
  • From the Center for Applied Genomics (J.T.G., R.G., H.H.), Center for Biomedical Informatics (M.I., J.L., P.S.W.), and Division of Cardiology (E.G.), Children’s Hospital of Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia (J.T.G., H.H.); Department of Genetics, Harvard Medical School, Boston, MA (A.G.B., K.I., J.G.H., E.M., S.R.D., C.S., J.S.); Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (J.G.H.);...
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-10-24
Volume
115
Issue
10
Pages
884-896
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.115.304458
PMC
PMC4209190
OpenAlex
W2144316033
Cited by
268
References
4
Citations by year
2026: 16 · 2025: 21 · 2024: 22 · 2023: 22 · 2022: 19 · 2021: 16 · 2020: 16 · 2019: 29 · 2018: 26 · 2017: 28 · 2016: 22 · 2015: 29 · 2014: 2
FWCI
17.69
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (UL1TR000142)
  • National Heart, Lung, and Blood Institute (U01HL098153, UM1HL098162, U01HL098123, U01HL098162, UM1HL098166, U01HL098188, U01HL098163, U01HL098147, T32HL007208)
  • National Human Genome Research Institute (U54HG006504)
  • National Institute of General Medical Sciences (T32GM007753)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
congenital heart disease, de novo copy number variants, CNV burden, 15q11.2, Jacobsen syndrome, CtBP2, ETS1, Nkx2.5, GATA4, novel genetic loci, trios
MeSH terms
Gene Frequency, Heart Defects, Congenital, Humans, Molecular Sequence Data, Cohort Studies, Case-Control Studies, Polymorphism, Single Nucleotide, Gene Regulatory Networks, DNA Copy Number Variations, Exome

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