Cardiomyopathy Clinical Trial
Official title:
Genetic Study of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
The purpose of this trial is to study the genetic and phenotypic aspects of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), and determine the impact of genetic testing in clinical practice.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC), is an inherited
myocardial disease that predominantly affects the right ventricle (RV) and the estimated
prevalence in the general population ranges from 1 to 5 in 1000. It is characterized
histopathologically by fibro-fatty myocardial replacement and clinically by ventricular
arrhythmia that may lead to sudden death, especially in young people and athletes. Clinical
diagnosis is based on diagnostic criteria proposed by the International Task Force of the
European Society of Cardiology and International Society and Federation of Cardiology (Task
Force 1994), but is often difficult due to a broad spectrum of clinical features and a lond
period of concealed cardiac expression, with delayed diagnosis.
ARVC/D is familial in 30 to 50% and is typically transmitted as an autosomal dominant trait
with variable penetrance. In the past years, the identification of causative mutations in
plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2),
desmocollin-2 (DSC2) has fostered the view that ARVC/D is a disorder of the desmosome and
provided new insight into its pathogenesis.
The major recent advance in the molecular genetics of ARVD/C might lead to important
clinical impact through early and correct diagnosis in patients and relatives, and through
potential genotype-phenotype correlations. This key-issue requires first to clarify the
optimal molecular strategy, and its efficiency. Such a systematic, detailed and
comprehensive mutation screening study is not available until now.
Aim:
Study the genetic and phenotypic aspects of Arrhythmogenic Right Ventricular
Dysplasia/Cardiomyopathy (ARVD/C), and determine the impact of genetic testing in clinical
practice.
Methods:
The study was approved by the Pitié-Salpétriêre Hospital ethical committee (CPPRB) and
written informed consent was obtained from all participating individuals, recruited in
France.
A cohort of 100 unrelated patients with ARVD/C will be recruited. Clinical evaluation will
include clinical history, family history, blood sample for DNA analysis 12-lead ECG,
signal-average ECG, 24-hour ambulatory ECG, transthoracic echocardiography, MRI and/or
radionuclide scintigraphy, and contrast angiography when possible. A clinical diagnosis of
ARVD/C is made according to the established European Society of Cardiology / International
Society and Federation of Cardiology Task Force major and minor criteria (Task Force 1994).
All available relatives will be proposed for enrollment in the study with blood sample for
DNA analysis and non invasive cardiac examination, including 12-lead ECG, signal-average
ECG, and transthoracic echocardiography.
Mutational analysis of the five genes encoding desmosomal genes will be performed in all
index cases (in plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2). When
mutations will be identified, available relatives will be analysed. In index cases without
desmosomal mutation, additional analyses will be performed according to a candidate gene
strategy and, when possible, through a genome wide approach and linkage analyses.
Expected results:
Determine the genetic origin in patients with ARVD/C whatever the familial context.
Determine a molecular strategy for routine genetic testing. Determine the impact of genetic
testing as a diagnostic test in patients and relatives.
Determine the impact of genetics as a prognostic tool, through phenotype-genotype analyses.
Determine the natural evolution of the disease in relatives, and the penetrance.
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Observational Model: Cohort, Time Perspective: Prospective
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