Human Genetics

, Volume 133, Issue 1, pp 11–27

The contribution of de novo and rare inherited copy number changes to congenital heart disease in an unselected sample of children with conotruncal defects or hypoplastic left heart disease

  • Dorothy Warburton
  • Michael Ronemus
  • Jennie Kline
  • Vaidehi Jobanputra
  • Ismee Williams
  • Kwame Anyane-Yeboa
  • Wendy Chung
  • Lan Yu
  • Nancy Wong
  • Danielle Awad
  • Chih-yu Yu
  • Anthony Leotta
  • Jude Kendall
  • Boris Yamrom
  • Yoon-ha Lee
  • Michael Wigler
  • Dan Levy
Original Investigation

DOI: 10.1007/s00439-013-1353-9

Cite this article as:
Warburton, D., Ronemus, M., Kline, J. et al. Hum Genet (2014) 133: 11. doi:10.1007/s00439-013-1353-9

Abstract

Congenital heart disease (CHD) is the most common congenital malformation, with evidence of a strong genetic component. We analyzed data from 223 consecutively ascertained families, each consisting of at least one child affected by a conotruncal defect (CNT) or hypoplastic left heart disease (HLHS) and both parents. The NimbleGen HD2-2.1 comparative genomic hybridization platform was used to identify de novo and rare inherited copy number variants (CNVs). Excluding 10 cases with 22q11.2 DiGeorge deletions, we validated de novo CNVs in 8 % of 148 probands with CNTs, 12.7 % of 71 probands with HLHS and none in 4 probands with both. Only 2 % of control families showed a de novo CNV. We also identified a group of ultra-rare inherited CNVs that occurred de novo in our sample, contained a candidate gene for CHD, recurred in our sample or were present in an affected sibling. We confirmed the contribution to CHD of copy number changes in genes such as GATA4 and NODAL and identified several genes in novel recurrent CNVs that may point to novel CHD candidate loci. We also found CNVs previously associated with highly variable phenotypes and reduced penetrance, such as dup 1q21.1, dup 16p13.11, dup 15q11.2-13, dup 22q11.2, and del 2q23.1. We found that the presence of extra-cardiac anomalies was not related to the frequency of CNVs, and that there was no significant difference in CNV frequency or specificity between the probands with CNT and HLHS. In agreement with other series, we identified likely causal CNVs in 5.6 % of our total sample, half of which were de novo.

Supplementary material

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Supplementary material 1 (DOCX 14 kb)
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Supplementary material 2 (JPG 86 kb)
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Supplementary material 3 (JPG 57 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Dorothy Warburton
    • 1
  • Michael Ronemus
    • 2
  • Jennie Kline
    • 3
  • Vaidehi Jobanputra
    • 4
  • Ismee Williams
    • 5
  • Kwame Anyane-Yeboa
    • 5
  • Wendy Chung
    • 5
    • 6
  • Lan Yu
    • 5
  • Nancy Wong
    • 7
  • Danielle Awad
    • 7
  • Chih-yu Yu
    • 5
  • Anthony Leotta
    • 2
  • Jude Kendall
    • 2
  • Boris Yamrom
    • 2
  • Yoon-ha Lee
    • 2
  • Michael Wigler
    • 2
  • Dan Levy
    • 2
  1. 1.Departments of Pediatrics and Genetics and DevelopmentColumbia UniversityNew YorkUSA
  2. 2.Cold Spring Harbor LaboratoriesCold Spring HarborUSA
  3. 3.Department of Epidemiology, Imprints Center, New York State Psychiatric Institute, Mailman School of Public Health and the Sergievsky CenterColumbia UniversityNew YorkUSA
  4. 4.Department of PathologyColumbia UniversityNew YorkUSA
  5. 5.Department of PediatricsColumbia UniversityNew YorkUSA
  6. 6.Department of MedicineColumbia UniversityNew YorkUSA
  7. 7.Department of EpidemiologyColumbia UniversityNew YorkUSA