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

Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis. To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD. 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. 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.

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 ，Warburton D ，Brueckner M ，Seidman C ，Goldmuntz E ，Gelb BD ，Lifton R ，Seidman J ，Hakonarson H ，Chung WK ... -  《-》

Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease.

Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHD had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 × 10(-5)). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in ~5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., HAND2 and GJA5). Rare genic deletions contribute ~4% of the population-attributable risk of sporadic CHD. Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHD trios exhibit paternal origin bias.

Soemedi R ，Wilson IJ ，Bentham J ，Darlay R ，Töpf A ，Zelenika D ，Cosgrove C ，Setchfield K ，Thornborough C ，Granados-Riveron J ，Blue GM ，Breckpot J ，Hellens S ，Zwolinkski S ，Glen E ，Mamasoula C ，Rahman TJ ，Hall D ，Rauch A ，Devriendt K ，Gewillig M ，O' Sullivan J ，Winlaw DS ，Bu'Lock F ，Brook JD ，Bhattacharya S ，Lathrop M ，Santibanez-Koref M ，Cordell HJ ，Goodship JA ，Keavney BD ... -  《-》

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 CY ，Leotta A ，Kendall J ，Yamrom B ，Lee YH ，Wigler M ，Levy D ... -  《-》

Rare de novo copy number variants in patients with congenital pulmonary atresia.

Xie L ，Chen JL ，Zhang WZ ，Wang SZ ，Zhao TL ，Huang C ，Wang J ，Yang JF ，Yang YF ，Tan ZP ... -  《PLoS One》

Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival.

Copy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and are overrepresented in children with congenital heart disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD, and to evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival. These cases are derived from a prospective cohort of patients with nonsyndromic CHD (n = 422) identified before first surgery. Healthy pediatric controls (n = 500) were obtained from the electronic Medical Records and Genetic Epidemiology Network, and CNV frequency was contrasted for CHD cases and controls. CNVs were determined algorithmically; subsequently screened for >95% overlap between 2 methods, size (>300 kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs); and separately validated by quantitative polymerase chain reaction. Survival likelihoods for cases were calculated using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival. Children with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared with pediatric controls (12.1% vs 5.0%; P = .00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (hazard ratio, 3.42; 95% confidence interval, 1.66-7.09; P = .00090) with confounder adjustment. We confirm that children with isolated CHD have a greater burden of rare/large CNVs. We report a novel finding that these CNVs are associated with an adjusted 2.55-fold increased risk of death or transplant. These data suggest that CNV burden is an important modifier of survival after surgery for CHD.

Kim DS ，Kim JH ，Burt AA ，Crosslin DR ，Burnham N ，Kim CE ，McDonald-McGinn DM ，Zackai EH ，Nicolson SC ，Spray TL ，Stanaway IB ，Nickerson DA ，Heagerty PJ ，Hakonarson H ，Gaynor JW ，Jarvik GP ... -  《-》