Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease

Abstract

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.

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta

“…Thus, TGA could result from a genetic predisposition related to many low impact, mostly inherited, variants associated to environmental factors. The frequency of de novo CNVs identified in patients with ToF (6.6%) is broadly similar to previously reported frequencies 11,21 considering the differences in the arrays and analysis pipelines between the studies. For example, Greenway et al 11 reported 10% of de novo CNVs in their ToF patients' cohort, which is slightly more than what we observed.…”

“…Recurrent deletions and duplications at this locus have been associated with both syndromic and nonsyndromic forms of CHD, including ToF. 11,21,36 Because the GJA5 mutant mice exhibit a wide range of CHD, among them conotruncal defects, 37 the gene seems to be a good candidate for the cardiac malformations, although no point mutations have been identified in patients yet.…”

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

“…Genome-wide [20][21][22] and gene-centric 23 copy number variants (CNV) were tested on a series of CHD with criteria to infer causality based either on de novo deletion/duplication in sporadic cases or familial segregation in multiplex cases. These studies could confirm the involvement of known CHD genes and discover new genes and genomic regions.…”

Reproductive Fitness and Genetic Transmission of Tetralogy of Fallot in the Molecular Age

“…[5][6][7][8][9][10][11] Rare CNVs 7 and syndromal (extracardiac) features 7,12 could influence reproductive fitness and transmission patterns in TOF, as is the case with 22q11.2 deletions and the associated 22q11.2 deletion syndrome (22q11.2DS). [13][14][15][16][17][18] Furthermore, an understanding of typical familial segregation patterns and other aspects of family history would help with the interpretation of emerging and novel molecular genetic risk factors (both de novo and inherited) for TOF.…”