Human gene copy number spectra analysis in congenital heart malformations

• Published in: Physiological genomics Vol. 44; no. 9; pp. 518 - 541
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2012
• Subjects: Adult; Aged; Algorithms; Aorta; Biological Specimen Banks; Canals; Case-Control Studies; Child; Congenital defects; copy number; Dimethylaniline monooxygenase (N-oxide-forming); DNA Copy Number Variations; Female; Fetuses; Gene Dosage; Gene Expression Profiling - methods; Gene frequency; Genetic Predisposition to Disease; Heart; Heart Defects, Congenital - diagnosis; Heart Defects, Congenital - genetics; Heart diseases; Humans; Male; Middle Aged; Models, Genetic; Models, Statistical; Oligonucleotide Array Sequence Analysis; Pediatrics; Phenotype; Phenotyping; Registries; Risk Assessment; Risk Factors; Runx1 protein; Stenosis; Tbx1 protein; tetralogy of Fallot; Young Adult
• ISSN: 1094-8341; 1531-2267; 1531-2267
• DOI: 10.1152/physiolgenomics.00013.2012

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.