title: 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: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Daniel Seung
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Wash.
authors.forename: Jerry H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Wash.
authors.forename: Amber A
authors.initials: AA
authors.lastname: Burt
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Wash; Department of Genome Sciences, University of Washington, Seattle, Wash.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Nancy
authors.initials: N
authors.lastname: Burnham
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.affiliation: Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Donna M
authors.initials: DM
authors.lastname: McDonald-McGinn
authors.affiliation: Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.affiliation: Division of Cardiothoracic Anesthesiology, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Nicolson
authors.affiliation: Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Spray
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Wash.
authors.forename: Ian B
authors.initials: IB
authors.lastname: Stanaway
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Wash.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Wash.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Heagerty
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: J William
authors.initials: JW
authors.lastname: Gaynor
authors.affiliation: 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.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
mesh_terms: D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D057286:Electronic Health Records; D005260:Female; D018628:Gene Dosage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery*; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors
chemical_list: D005819:Genetic Markers
keywords: congenital heart disease; copy number variation; genetics; survival