Faculty Collaboration Database

Human gene copy number spectra analysis in congenital heart malformations. Physiol Genomics 2012 May 01;44(9):518-41

Date

02/10/2012

Pubmed ID

22318994

Pubmed Central ID

PMC3426426

DOI

10.1152/physiolgenomics.00013.2012

Scopus ID

2-s2.0-84862128193 (requires institutional sign-in at Scopus site)   84 Citations

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 phenotype-gene 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.

Author List

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

Authors

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin
Donna K. Mahnke Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Aoy Tomita Mitchell PhD Professor in the Surgery department at Medical College of Wisconsin
Michael Edward Mitchell MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Algorithms
Biological Specimen Banks
Case-Control Studies
Child
DNA Copy Number Variations
Female
Gene Dosage
Gene Expression Profiling
Genetic Predisposition to Disease
Heart Defects, Congenital
Humans
Male
Middle Aged
Models, Genetic
Models, Statistical
Oligonucleotide Array Sequence Analysis
Phenotype
Registries
Risk Assessment
Risk Factors
Young Adult