Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.

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.

journal_name

Circ Res

journal_title

Circulation research

authors

Glessner JT,Bick AG,Ito K,Homsy J,Rodriguez-Murillo L,Fromer M,Mazaika E,Vardarajan B,Italia M,Leipzig J,DePalma SR,Golhar R,Sanders SJ,Yamrom B,Ronemus M,Iossifov I,Willsey AJ,State MW,Kaltman JR,White PS,Shen Y

doi

10.1161/CIRCRESAHA.115.304458

subject

Has Abstract

pub_date

2014-10-24 00:00:00

pages

884-896

issue

10

eissn

0009-7330

issn

1524-4571

journal_volume

115

pub_type

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