Document Detail

Effect of copy number variants on outcomes for infants with single ventricle heart defects.
MedLine Citation:
PMID:  24021551     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Human genomes harbor copy number variants (CNVs), which are regions of DNA gains or losses. Although pathogenic CNVs are associated with congenital heart disease (CHD), their effect on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle physiology were associated with inferior neurocognitive and somatic growth outcomes.
METHODS AND RESULTS: Genomic DNAs from 223 subjects of 2 National Heart, Lung, and Blood Institute-sponsored randomized clinical trials in infants with single ventricle CHD and 270 controls from The Cancer Genome Atlas project were analyzed for rare CNVs>300 kb using array comparative genomic hybridization. Neurocognitive and growth outcomes at 14 months from the CHD trials were compared among subjects with and without pathogenic CNVs. Putatively pathogenic CNVs, comprising 25 duplications and 6 deletions, had a prevalence of 13.9%, significantly greater than the 4.4% rate of such CNVs among controls. CNVs associated with genomic disorders were found in 13 cases but not in controls. Several CNVs likely to be causative of single ventricle CHD were observed, including aberrations altering the dosage of GATA4, MYH11, and GJA5. Subjects with pathogenic CNVs had worse linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. A minority of children with pathogenic CNVs were noted to be dysmorphic on clinical genetics examination.
CONCLUSIONS: Pathogenic CNVs seem to contribute to the cause of single ventricle forms of CHD in ≥10% of cases and are clinically subtle but adversely affect outcomes in children harboring them.
Abigail S Carey; Li Liang; Jonathan Edwards; Tracy Brandt; Hui Mei; Andrew J Sharp; Daphne T Hsu; Jane W Newburger; Richard G Ohye; Wendy K Chung; Mark W Russell; Jill A Rosenfeld; Lisa G Shaffer; Michael K Parides; Lisa Edelmann; Bruce D Gelb
Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-09-10
Journal Detail:
Title:  Circulation. Cardiovascular genetics     Volume:  6     ISSN:  1942-3268     ISO Abbreviation:  Circ Cardiovasc Genet     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-10-16     Completed Date:  2014-05-14     Revised Date:  2014-10-09    
Medline Journal Info:
Nlm Unique ID:  101489144     Medline TA:  Circ Cardiovasc Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  444-51     Citation Subset:  IM    
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MeSH Terms
Case-Control Studies
Cohort Studies
Comparative Genomic Hybridization
Connexins / genetics
DNA Copy Number Variations*
GATA4 Transcription Factor / genetics
Genome, Human
Heart Defects, Congenital / epidemiology,  genetics*,  pathology
Myosin Heavy Chains / genetics
Grant Support
Reg. No./Substance:
0/Connexins; 0/GATA4 Transcription Factor; 0/GATA4 protein, human; 0/MYH11 protein, human; 0/connexin 40; EC Heavy Chains

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