Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy.
Circ Cardiovasc Genet
; 6(6): 533-42, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-24070718
ABSTRACT
BACKGROUND:
Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC. METHODS ANDRESULTS:
The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years [22-52]) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively.CONCLUSIONS:
Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Morte Súbita Cardíaca
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Displasia Arritmogênica Ventricular Direita
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Desmossomos
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Mutação
Tipo de estudo:
Etiology_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:
Circ Cardiovasc Genet
Assunto da revista:
ANGIOLOGIA
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CARDIOLOGIA
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GENETICA MEDICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Itália