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

作者：Joseph Glessner, Alexander G. Bick, Kaoru Ito, Jason Homsy, Laura Rodriguez‐Murillo, Menachem Fromer, Erica Mazaika, Badri N. Vardarajan, Michael J. Italia, Jeremy Leipzig, Steven R. DePalma, Ryan Golhar, Stephan Sanders, Boris Yamrom, Michael Ronemus, Ivan Iossifov, A. Jeremy Willsey, Matthew W. State, Jonathan R. Kaltman, Peter S. White, Yufeng Shen, Dorothy Warburton, Martina Brueckner, Christine E. Seidman, Elizabeth Goldmuntz, Bruce D. Gelb, Richard P. Lifton, Jonathan G. Seidman, Håkon Håkonarson, Wendy K. Chung · 发表于：Circulation Research · 年份：2014 · DOI：10.1161/circresaha.115.304458 · 被引用次数：278 · 研究领域：Congenital heart defects research、Genomic variations and chromosomal abnormalities、Genomics and Rare Diseases

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 demons...