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

Abstract

Objectives Copy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and over-represented in children with congenital heart disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD and evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival. Methods These cases are derived from a prospective cohort of non-syndromic CHD patients (n=422) ascertained prior to their first surgery. Healthy pediatric controls (n=500) were obtained from the electronic Medical Records and Genetic Epidemiology (eMERGE) Network and CNV frequency was contrasted for CHD cases and controls. CNVs were algorithmically determined, subsequently screened for >95% overlap between two methods, size (>300kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs), and separately validated with quantitative-PCR. Survival likelihoods were calculated for cases using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival. Results Children with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared to pediatric controls (12.1% vs. 5.0%, P=0.00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (HR=3.42, 95% CI: 1.66-7.09, P=0.00090) with confounder adjustment. Conclusions 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.

Assessment of large copy number variants in patients with apparently isolated congenital left‐sided cardiac lesions reveals clinically relevant genomic events

“…cardiac instability); nonetheless, our data would suggest that in the absence of clear syndromic, dysmorphic, or extra-cardiac features, as assessed by primary physicians, a genomic and genetic evaluation is still warranted, especially in cases where a full clinical genetic evaluation is not readily available. The potential clinical yield of assessing large CNVs appears to be applicable to most cases of LSL with or without overt extra-cardiac features, a finding consistent with a recent study of CNVs in isolated CHD [Kim et al 2016]. …”

“…Many of the CNVs have also been observed among apparently unaffected population-based controls, implying that penetrance is incomplete, making genetic counselling of families with such CNVs more difficult. Likely pathogenic CNVs have been observed more often in individuals with CHD but without developmental delays, dysmorphic features, or other birth defects (hereafter called isolated CHDs) than in children without CHD [Kim et al 2016], but the utility of CNV analysis in this group of individuals has remained equivocal; in turn, this has meant that genetic testing for CNVs in isolated CHDs controversial [Connor et al 2014]. …”

Genetics and Genomics of Congenital Heart Disease

“…An increased burden of CNVs was also detected in non-syndromic patients with mild-to-moderate severity CHD 47 . The availability of chromosomal microarray testing as a standard clinical test has increased the awareness of the contribution of CNVs to congenital heart disease, and clinical and research-based testing suggests that CNVs contribute to 10–15% of CHD 48 . As previously noted, given the inherent limitations of most commonly used platforms for CNV detection for optimal sensitivity, the contribution of CNVs to disease phenotypes may underestimate their contribution 31 .…”

Trends in Congenital Heart Disease

“…The next decade will bring breakthroughs in understanding the sources for the remaining variance in neurocognitive outcomes. 58,59 Using whole genome sequencing and other genetic technologies, we will better understand the role of genetic and epigenetic contributions to ND disabilities in CHD patients. In-exome sequencing of CHD parent-offspring trios gathered in the Pediatric Cardiac Genomics Consortium recently demonstrated an excess of protein-damaging de novo mutations; such mutations occurred most frequently in genes highly expressed in the developing heart and brain, and affected genes involved in morphogenesis, chromatin modification, and transcriptional regulation.…”