title: 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.
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.
authors: Departments of Pediatrics and Genetics and Development, Columbia University, New York, NY, USA, dw9@columbia.edu.
authors: Dorothy
authors: D
authors: Warburton
authors: Michael
authors: M
authors: Ronemus
authors: Jennie
authors: J
authors: Kline
authors: Vaidehi
authors: V
authors: Jobanputra
authors: Ismee
authors: I
authors: Williams
authors: Kwame
authors: K
authors: Anyane-Yeboa
authors: Wendy
authors: W
authors: Chung
authors: Lan
authors: L
authors: Yu
authors: Nancy
authors: N
authors: Wong
authors: Danielle
authors: D
authors: Awad
authors: Chih-Yu
authors: CY
authors: Yu
authors: Anthony
authors: A
authors: Leotta
authors: Jude
authors: J
authors: Kendall
authors: Boris
authors: B
authors: Yamrom
authors: Yoon-Ha
authors: YH
authors: Lee
authors: Michael
authors: M
authors: Wigler
authors: Dan
authors: D
authors: Levy
mesh_terms: D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D015894:Genome, Human; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics*; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: C491268:CFC1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C501109:NOMO3 protein, human
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