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Genetics of arrhythmogenic right ventricular cardiomyopathy--status quo and future perspectives
M Paul1, E Schulze-Bahr, G Breithardt
1Universitätsklinikum Münster, Medizinische Klinik und Poliklinik C-Kardiologie und Angiologie, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany. mapaul@uni-muenster.de
Insights
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic heart disorder. Research highlights genetic mutations as key to ARVC
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder.
- ARVC is a significant cause of ventricular tachyarrhythmias and sudden cardiac death in young individuals.
- Diagnosis of ARVC is challenging despite established criteria.
Purpose of the Study:
- To review the role of molecular genetics in the pathogenesis of ARVC.
- To discuss current understanding of genetic alterations underlying ARVC.
- To explore the implications of genetic findings for diagnosis and management.
Main Methods:
- Review of linkage analyses in families affected by ARVC.
- Analysis of reported genetic mutations in ARVC.
- Comparison of different inheritance patterns and phenotypes (autosomal-dominant, autosomal-recessive).
Main Results:
- Growing evidence supports genetic alterations in ARVC, predominantly autosomal-dominant inheritance.
- Two autosomal-recessive forms identified: Naxos disease (hair/skin abnormalities, severe course) and another with lens opacities.
- Specific mutations identified in plakoglobin and cardiac ryanodine receptor genes.
Conclusions:
- Genetic factors play a crucial role in ARVC pathogenesis.
- Distinct genetic forms of ARVC exhibit unique phenotypes and inheritance patterns.
- Future genetic testing may improve ARVC diagnosis, understanding, and management.
Abstract:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder of unknown origin. In recent years, the disease has been recognized as a major cause of ventricular tachyarrhythmias and sudden cardiac death in young patients with apparently normal hearts. Although characteristic structural, imaging and electrocardiographic features are included in a proposed catalogue of diagnostic criteria, the correct diagnosis of ARVC often remains difficult. Much effort has been undertaken to enlarge the knowledge on pathophysiological mechanisms of the disease. The role of molecular genetics for the pathogenesis of ARVC is discussed in the following review. On the basis of linkage analyses in large families affected by ARVC, there is growing evidence for genetic alterations in ARVC, which, in the majority of chromosomal loci (seven) reported so far, follow a Mendelian autosomal-dominant pattern of inheritance with variable penetrance and polymorphic phenotype. Besides this, two autosomal-recessive forms of ARVC are known. These can be differentiated from the autosomal-dominant forms not only in terms of the mode of inheritance but also as to their specific phenotype: patients with Naxos disease exhibit characteristic hair and skin abnormalities and experience a more severe course of disease. Patients with another autosomal-recessive form display the typical but milder signs of ARVC together with opacifications of the crystalline lens. So far, two mutations in cardiac genes responsible for the development of ARVC have been reported. A homozygous two base pair deletion in the gene encoding for the cytoskeletal protein plakoglobin seems to account for the evolution of Naxos disease. The second mutation affecting the cardiac ryanodine receptor gene was found in patients with ARVC-2. Routine genetic testing of patients or relatives with a suspected diagnosis of ARVC is not available at present but may become the future gold standard with potential implications for a better understanding of the pathogenesis and management of the disease.