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Clinical Trial
. 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

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Free PMC article
Clinical Trial

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

Joseph T Glessner et al. Circ Res. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Comparison of SNP array and WES platforms in detection of the 42 validated de novo CNVs in the subset of 233 probands studied by both technologies. 10 of the 42 were detected by both methods, 32 were called by one method. The figures below the dotted line show the number of CNVs that were below the detection limits of the second platform (CNVs that span <10 SNPs on SNP arrays or <3 exons on WES) and hence could not have been called. The figures above the dotted line show the number of CNVs with sufficient SNPs and/or exons to enable high confirmation rates, but that were not called.
Figure 2
Figure 2
Network analysis of CNV loci genes. Two networks of direct protein-protein interactions, (A) NKX2.5/Gata4 and (B) ETS1/JUN/TOP2A, were consistently identified in the DAPPLE de novo CNV loci analysis. P-values from the genes highly expressed in the developing heart, the most restrictive gene set list, are presented here. (C) The ETS1/JUN/TOP2A network was significantly elaborated upon by incorporating genes with deleterious de novo point mutations and indels in the WES exome sequencing analysis in addition to the CNV loci. Of note, two probands had de novo ETS1 variants (one CNV and one frameshift), two probands had de novo SMAD2 variants (a splice site mutation and a highly conserved missense variant) and two probands had de novo ELN variants (both Williams syndrome CNVs).

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