title: Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome.
abstract: BACKGROUND
  Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations characterized by severe underdevelopment of left heart structures, resulting in a univentricular circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects has been mounting. However, the functional effects of such CNVs have not been examined, particularly in cases where the variant of interest is found in only a single patient.
  
  
  RESULTS
  Whole-genome SNP microarrays were employed to detect CNVs in two patient cohorts (N = 70 total) predominantly diagnosed with some form of nonsyndromic HLHS. We discovered 16 rare or private variants adjacent to or overlapping 20 genes associated with cardiovascular or premature lethality phenotypes in mouse knockout models. We evaluated the impact of selected variants on the expression of nine of these genes through quantitative PCR on cDNA derived from patient heart tissue. Four genes displayed significantly altered expression in patients with an overlapping or proximal CNV verses patients without such CNVs.
  
  
  CONCLUSIONS
  Rare and private genomic imbalances perturb transcription of genes that potentially affect cardiogenesis in a subset of nonsyndromic HLHS patients.
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Glidewell
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Department of Pediatrics, Children's Hospital Colorado, Aurora, Colorado, USA.
authors.forename: Shelley D
authors.initials: SD
authors.lastname: Miyamoto
authors.affiliation: Department of Pediatrics, University of California, San Diego, California, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Grossfeld
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Clouthier
authors.affiliation: PathGroup, Nashville, Tennessee, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Coldren
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Stearman
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Geraci
mesh_terms: D000818:Animals; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005260:Female; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics*; D008297:Male; D008390:Markov Chains; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic
chemical_list: D018076:DNA, Complementary
keywords: cardiovascular diseases; congenital; genetics; heart defects