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 journalArticle

58 Citations (Scopus)

Abstract

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
Volume44
Issue number9
DOIs
StatePublished - May 1 2012
Externally publishedYes

Fingerprint

Gene Dosage
Congenital Heart Defects
Heart Diseases
Spectrum Analysis
Tetralogy of Fallot
Gene Frequency
Truncus Arteriosus
Genes
Aortic Valve Stenosis
Chromosome Aberrations
Coronary Artery Disease
Pathologic Constriction
Pediatrics
Phenotype
Control Groups
Population

Keywords

  • Congenital heart disease
  • Copy number variation
  • Genetics

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Tomita-Mitchell, A., Mahnke, D. K., Struble, C. A., Tuffnell, M. E., Stamm, K. D., Hidestrand, M., ... Mitchell, M. E. (2012). Human gene copy number spectra analysis in congenital heart malformations. Physiological Genomics, 44(9), 518-541. https://doi.org/10.1152/physiolgenomics.00013.2012

Human gene copy number spectra analysis in congenital heart malformations. / Tomita-Mitchell, Aoy; Mahnke, Donna K.; Struble, Craig A.; Tuffnell, Maureen E.; Stamm, Karl D.; Hidestrand, Mats; Harris, Susan E.; Goetsch, Mary A.; Simpson, Pippa M.; Bick, David P.; Broeckel, Ulrich; Pelech, Andrew N; Tweddell, James S.; Mitchell, Michael E.

In: Physiological Genomics, Vol. 44, No. 9, 01.05.2012, p. 518-541.

Research output: Contribution to journalArticle

Tomita-Mitchell, A, Mahnke, DK, Struble, CA, Tuffnell, ME, Stamm, KD, Hidestrand, M, Harris, SE, Goetsch, MA, Simpson, PM, Bick, DP, Broeckel, U, Pelech, AN, Tweddell, JS & Mitchell, ME 2012, 'Human gene copy number spectra analysis in congenital heart malformations', Physiological Genomics, vol. 44, no. 9, pp. 518-541. https://doi.org/10.1152/physiolgenomics.00013.2012
Tomita-Mitchell A, Mahnke DK, Struble CA, Tuffnell ME, Stamm KD, Hidestrand M et al. Human gene copy number spectra analysis in congenital heart malformations. Physiological Genomics. 2012 May 1;44(9):518-541. https://doi.org/10.1152/physiolgenomics.00013.2012
Tomita-Mitchell, Aoy ; Mahnke, Donna K. ; Struble, Craig A. ; Tuffnell, Maureen E. ; Stamm, Karl D. ; Hidestrand, Mats ; Harris, Susan E. ; Goetsch, Mary A. ; Simpson, Pippa M. ; Bick, David P. ; Broeckel, Ulrich ; Pelech, Andrew N ; Tweddell, James S. ; Mitchell, Michael E. / Human gene copy number spectra analysis in congenital heart malformations. In: Physiological Genomics. 2012 ; Vol. 44, No. 9. pp. 518-541.
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