Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study.

Details

Serval ID
serval:BIB_061FF812753A
Type
Article: article from journal or magazin.
Collection
Publications
Title
Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study.
Journal
Circulation
Author(s)
Cox M.G., van der Zwaag P.A., van der Werf C., van der Smagt J.J., Noorman M., Bhuiyan Z.A., Wiesfeld A.C., Volders P.G., van Langen I.M., Atsma D.E., Dooijes D., van den Wijngaard A., Houweling A.C., Jongbloed J.D., Jordaens L., Cramer M.J., Doevendans P.A., de Bakker J.M., Wilde A.A., van Tintelen J.P., Hauer R.N.
ISSN
1524-4539 (Electronic)
ISSN-L
0009-7322
Publication state
Published
Issued date
14/06/2011
Peer-reviewed
Oui
Volume
123
Number
23
Pages
2690-2700
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce.
One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations).
Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.

Keywords
Adolescent, Adult, Arrhythmogenic Right Ventricular Dysplasia/genetics, Arrhythmogenic Right Ventricular Dysplasia/mortality, Arrhythmogenic Right Ventricular Dysplasia/pathology, Asymptomatic Diseases/mortality, Death, Sudden, Cardiac/epidemiology, Desmosomes/pathology, Family, Female, Follow-Up Studies, Genotype, Humans, Male, Middle Aged, Netherlands/epidemiology, Phenotype, Predictive Value of Tests, Risk Factors, Tachycardia, Ventricular/genetics, Tachycardia, Ventricular/mortality, Tachycardia, Ventricular/pathology, Ventricular Fibrillation/genetics, Ventricular Fibrillation/mortality, Ventricular Fibrillation/pathology, Young Adult
Pubmed
Web of science
Open Access
Yes
Create date
01/03/2018 15:22
Last modification date
20/08/2019 12:28
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