Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome

Steven C. Glidewell, Shelley D. Miyamoto, Paul D. Grossfeld, David E. Clouthier, Christopher D. Coldren, Robert Stearman, Mark W. Geraci

Research output: Contribution to journalArticle

4 Citations (Scopus)

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. Methods and 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. Conclusion: Rare and private genomic imbalances perturb transcription of genes that potentially affect cardiogenesis in a subset of nonsyndromic HLHS patients.

Original languageEnglish (US)
Pages (from-to)682-689
Number of pages8
JournalClinical and Translational Science
Volume8
Issue number6
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Hypoplastic Left Heart Syndrome
Genes
Overlapping Genes
Inborn Genetic Diseases
Congenital Heart Defects
Knockout Mice
Transcription
Microarrays
Single Nucleotide Polymorphism
Mountings
Complementary DNA
Genome
Phenotype
Gene Expression
Polymerase Chain Reaction
Tissue
Defects

Keywords

  • Cardiovascular diseases
  • Congenital
  • Genetics
  • Heart defects

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Glidewell, S. C., Miyamoto, S. D., Grossfeld, P. D., Clouthier, D. E., Coldren, C. D., Stearman, R., & Geraci, M. W. (2015). Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome. Clinical and Translational Science, 8(6), 682-689. https://doi.org/10.1111/cts.12340

Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome. / Glidewell, Steven C.; Miyamoto, Shelley D.; Grossfeld, Paul D.; Clouthier, David E.; Coldren, Christopher D.; Stearman, Robert; Geraci, Mark W.

In: Clinical and Translational Science, Vol. 8, No. 6, 01.12.2015, p. 682-689.

Research output: Contribution to journalArticle

Glidewell, SC, Miyamoto, SD, Grossfeld, PD, Clouthier, DE, Coldren, CD, Stearman, R & Geraci, MW 2015, 'Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome', Clinical and Translational Science, vol. 8, no. 6, pp. 682-689. https://doi.org/10.1111/cts.12340
Glidewell, Steven C. ; Miyamoto, Shelley D. ; Grossfeld, Paul D. ; Clouthier, David E. ; Coldren, Christopher D. ; Stearman, Robert ; Geraci, Mark W. / Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome. In: Clinical and Translational Science. 2015 ; Vol. 8, No. 6. pp. 682-689.
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