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J Thorac Cardiovasc Surg. 2016 Apr;151(4):1147-51.e4. doi: 10.1016/j.jtcvs.2015.09.136. Epub 2015 Nov 10.

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

Author information

1
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Wash; Department of Genome Sciences, University of Washington, Seattle, Wash; Department of Biostatistics, University of Washington, Seattle, Wash.
2
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Wash.
3
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Wash.
4
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Wash; Department of Genome Sciences, University of Washington, Seattle, Wash.
5
Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa.
6
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa.
7
Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pa.
8
Division of Cardiothoracic Anesthesiology, The Children's Hospital of Philadelphia, Philadelphia, Pa.
9
Department of Genome Sciences, University of Washington, Seattle, Wash.
10
Department of Biostatistics, University of Washington, Seattle, Wash.
11
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Wash; Department of Genome Sciences, University of Washington, Seattle, Wash. Electronic address: pair@u.washington.edu.

Abstract

OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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.

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.

KEYWORDS:

congenital heart disease; copy number variation; genetics; survival

PMID:
26704054
PMCID:
PMC4801686
DOI:
10.1016/j.jtcvs.2015.09.136
[Indexed for MEDLINE]
Free PMC Article

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