{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T17:17:05Z","timestamp":1784567825150,"version":"3.55.0"},"reference-count":55,"publisher":"American Physiological Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiological Genomics"],"published-print":{"date-parts":[[2012,5,1]]},"abstract":"<jats:p>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 \u201cspectra\u201d 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 (\u2265200 kb) and losses (\u2265100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment ( P \u2264 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 \u2264 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.<\/jats:p>","DOI":"10.1152\/physiolgenomics.00013.2012","type":"journal-article","created":{"date-parts":[[2012,2,8]],"date-time":"2012-02-08T07:57:49Z","timestamp":1328687869000},"page":"518-541","source":"Crossref","is-referenced-by-count":93,"title":["Human gene copy number spectra analysis in congenital heart malformations"],"prefix":"10.1152","volume":"44","author":[{"given":"Aoy","family":"Tomita-Mitchell","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery;"},{"name":"Biotechnology and Bioengineering Center;"},{"name":"Human and Molecular Genetics Center;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna K.","family":"Mahnke","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery;"},{"name":"Biotechnology and Bioengineering 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