Human gene copy number spectra analysis in congenital heart malformations

Aoy Tomita-Mitchell, Donna K. Mahnke, Craig A. Struble, Maureen E. Tuffnell, Karl D. Stamm, Mats Hidestrand, Susan E. Harris, Mary A. Goetsch, Pippa M. Simpson, David P. Bick, Ulrich Broeckel, Andrew N Pelech, James S. Tweddell, Michael E. Mitchell

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency "spectra" to be computed over prespecified regions to determine phenotypegene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways.

Original languageEnglish (US)
Pages (from-to)518-541
Number of pages24
JournalPhysiological Genomics
Issue number9
StatePublished - May 1 2012
Externally publishedYes


  • Congenital heart disease
  • Copy number variation
  • Genetics

ASJC Scopus subject areas

  • Physiology
  • Genetics


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