Alternative titles; symbols
ORPHA: 217656; DO: 0110073;
Cytogenetic location: 2q32.1-q32.3 Genomic coordinates (GRCh38) : 2:182,100,001-196,600,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.1-q32.3 | Arrhythmogenic right ventricular dysplasia 4 | 602087 | Autosomal dominant | 2 |
Familial arrhythmogenic right ventricular dysplasia-4 (ARVD4) is characterized by progressive degeneration of the myocardium of the right ventricle, with focal necrosis of muscle cells followed by adipose and connective tissue replacement. The left ventricle may be partially involved. Patches of replacement tissue result in electrical instability and arrhythmias. Patients experience syncopal episodes, and sudden death may occur (summary by Rampazzo et al., 1997).
For phenotypic information and evidence of genetic heterogeneity in this disorder, see ARVD1 (107970).
Kirsch et al. (1993) described a family of Sicilian origin in which 2 sibs died suddenly in their teens and another had syncopal episodes. A brother died in his sleep at age 15 years, and a sister died at age 16 during basketball practice. Autopsy in the brother showed myocardial replacement with fibrous tissue; postmortem examination in the sister revealed massive replacement of the right ventricular myocardium by fatty tissue extending from the epicardium to the endocardium, with extensive fibrosis observed in the subendocardium of the ventricular wall and papillary muscle. The proband was a 16-year-old girl who reported lightheadedness and a near-syncopal episode at rest. Given her family history, she underwent extensive evaluation including cardiac catheterization, all of which showed normal results or was nondiagnostic. Analysis of endocardial biopsies taken at the time of catheterization showed no significant abnormalities in the left ventricular tissue, and 3 of 4 fragments from the right ventricle were also unremarkable; however, the remaining right ventricular fragment contained a cluster of fat cells and focal dense fibrosis. There was no evidence of inflammation or of myofiber necrosis or degeneration. The proband underwent prophylactic placement of an automatic implantable cardioverter-defibrillator (AICD). The authors noted that the family originated from Italy, where several families with arrhythmogenic right ventricular dysplasia (ARVD) and sudden death had been reported.
Rampazzo et al. (1997) studied 3 unrelated families with ARVD. Family 107 was the family of Sicilian ancestry originally described by Kirsch et al. (1993) in which there were 3 affected sibs; another sister had since been found to be clinically affected. In family 108, from Mantua in northern Italy, a father and 3 daughters were affected. One of the daughters experienced ventricular arrhythmias (Lown 4b) with left bundle branch block (LBBB), and the diagnosis was confirmed by angiographic study and cardiac biopsy. The other 3 patients had echocardiographic changes and late potentials on electrocardiogram (ECG); 2 were asymptomatic and 1 had ventricular arrhythmias. In family 109, from Udine in northern Italy, 2 brothers and their father were affected, and the paternal grandfather was reported to have died suddenly at age 51. One of the brothers had a syncopal episode while dancing and also reported cardiac arrhythmias. ECG monitoring revealed frequent arrhythmias (Lown 4b) and late potentials with LBBB, and ARVD was confirmed by myocardial biopsy, echocardiography, and electrophysiologic analysis. The other brother and their father were asymptomatic, but both showed echocardiographic changes typical of ARVD and late potentials on ECG. Rampazzo et al. (1997) noted that affected individuals in all 3 families exhibited the unusual finding of localized involvement of the left ventricle. In addition, patients with severe manifestations were invariably involved in sporting activities in their youth, suggesting that strenuous physical exercise might be dangerous for patients with ARVD.
In 3 unrelated families with ARVD, 1 of Sicilian origin (107) that was originally described by Kirsch et al. (1993), and 2 from northern Italy (108 and 109), Rampazzo et al. (1997) mapped a novel ARVD locus to 2q32.1-q32.3, within the chromosomal region including markers D2S152, D2S103, and D2S389. Affected members of the 3 families showed clinical features typical of ARVD according to the diagnostic criteria of McKenna et al. (1994).
Kirsch, L. R., Weinstock, D. J., Magid, M. S., Levin, A. R., Gold, J. P. Treatment of presumed arrhythmogenic right ventricular dysplasia in an adolescent. Chest 104: 298-300, 1993. [PubMed: 8325094] [Full Text: https://doi.org/10.1378/chest.104.1.298]
McKenna, W. J., Thiene, G., Nava, A., Fontaliran, F., Blomstrom-Lundqvist, C., Fontaine, G., Camerini, F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Brit. Heart J. 71: 215-218, 1994. [PubMed: 8142187] [Full Text: https://doi.org/10.1136/hrt.71.3.215]
Rampazzo, A., Nava, A., Miorin, M., Fonderico, P., Pope, B., Tiso, N., Livolsi, B., Zimbello, R., Thiene, G., Danieli, G. A. ARVD4, a new locus for arrhythmogenic right ventricular cardiomyopathy, maps to chromosome 2 long arm. Genomics 45: 259-263, 1997. [PubMed: 9344647] [Full Text: https://doi.org/10.1006/geno.1997.4927]