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

Warburton, D., Ronemus, M., Kline, J., Jobanputra, V., Williams, I., Anyane-Yeboa, K., Chung, W., Yu, L., Wong, N., Awad, D., Yu, C. Y., Leotta, A., Kendall, J., Yamrom, B., Lee, Y. H., Wigler, M., Levy, D. (January 2014) 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. Human Genetics, 133 (1). pp. 11-27. ISSN 1432-1203 (Electronic)0340-6717 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/23979609
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.

Item Type: Paper
Uncontrolled Keywords: Child, Preschool Comparative Genomic Hybridization DNA Copy Number Variations/*genetics Female Gene Deletion Gene Duplication Genome, Human Heart Defects, Congenital/*genetics Humans Hypoplastic Left Heart Syndrome/*genetics Infant Intercellular Signaling Peptides and Proteins/genetics/metabolism Intracellular Signaling Peptides and Proteins/genetics/metabolism Male Membrane Proteins/genetics/metabolism Reproducibility of Results
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > copy number variants
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > spontaneous copy number variation
CSHL Authors:
Communities: CSHL labs > Levy lab
CSHL labs > Wigler lab
CSHL Cancer Center Shared Resources > Instrumentation Service
CSHL Cancer Center Shared Resources > Next Generation Sequencing Service
Depositing User: Matt Covey
Date: January 2014
Date Deposited: 26 Dec 2014 16:14
Last Modified: 26 Dec 2014 16:14
PMCID: PMC3880624
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30990

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