Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries.
Int J Cardiol
; 204: 115-21, 2016 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-26655555
ABSTRACT
BACKGROUND:
Transposition of the great arteries (TGA) is an uncommon but severe congenital heart malformation of unknown etiology. Rare copy number variations (CNVs) have been implicated in other, more common conotruncal heart defects like tetralogy of Fallot (TOF), but there are as yet no CNV studies dedicated to TGA.METHODS:
Using high-resolution genome-wide microarrays and rigorous methods, we investigated CNVs in a group of prospectively recruited adults with TGA (n=101) from a single center. We compared rare CNV burden to well-matched cohorts of controls and TOF cases, adjudicating rarity using 10,113 independent population-based controls and excluding all subjects with 22q11.2 deletions. We identified candidate genes for TGA based on rare CNVs that overlapped the same gene in unrelated individuals, and pre-existing evidence suggesting a role in cardiac development.RESULTS:
The TGA group was significantly enriched for large rare CNVs (2.3-fold increase, p=0.04) relative to controls, to a degree comparable with the TOF group. Extra-cardiac features were not reliable predictors of rare CNV burden. Smaller rare CNVs helped to narrow critical regions for conotruncal defects at chromosomes 10q26 and 13q13. Established and novel candidate susceptibility genes identified included ACKR3, IFT57, ITGB8, KL, NF1, NKX1-2, RERE, SLC8A1, SOX18, and ULK1.CONCLUSIONS:
These data demonstrate a genome-wide role for rare CNVs in genetic risk for TGA. The findings provide further support for a genetically-related spectrum of congenital heart disease that includes TGA and TOF.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transposição dos Grandes Vasos
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Predisposição Genética para Doença
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Estudo de Associação Genômica Ampla
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Variações do Número de Cópias de DNA
Tipo de estudo:
Etiology_studies
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Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Int J Cardiol
Ano de publicação:
2016
Tipo de documento:
Article