Alternative titles; symbols
ORPHA: 217656; DO: 0110076;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p24.3 | Arrhythmogenic right ventricular dysplasia 8 | 607450 | Autosomal dominant | 3 | DSP | 125647 |
A number sign (#) is used with this entry because of evidence that arrhythmogenic right ventricular dysplasia-8 (ARVD8) is caused by heterozygous mutation in the gene encoding desmoplakin (DSP; 125647) on chromosome 6p24.
ARVD8 is characterized by progressive degeneration of the right ventricular myocardium. Patients may experience life-threatening cardiac arrhythmias and show depolarization, conduction, and repolarization defects on electrocardiography (Rampazzo et al., 2002).
For a general phenotypic description and a discussion of genetic heterogeneity of ARVD, see 107970.
Rampazzo et al. (2002) reported a 4-generation Italian family in which the proband experienced cardiac arrest at age 18 due to ventricular fibrillation during physical effort. Cardiac evaluation revealed depolarization, conduction, and repolarization abnormalities as well as right ventricular kinetic alterations, and he had ventricular arrhythmias including fibrillation and premature contractions. Familial analysis revealed 10 additional family members who all exhibited repolarization abnormalities as well as various other cardiac abnormalities, including sustained ventricular tachycardia in 2 patients. Cardiac symptoms ranged from mild to severe among the family members; there were 2 sudden deaths, at ages 15 and 65 years, and 1 patient died of heart failure at age 68 years. None of the family members exhibited woolly hair or skin changes.
Christensen et al. (2010) studied a patient (family L) with ARVD, who developed cardiac symptoms at age 22 years, including palpitations and syncope. He had depolarization and repolarization abnormalities on electrocardiography, as well as arrhythmias. Left ventricular ejection fraction was slightly decreased, at 50%; structural and/or functional alterations were tabulated but not reported in detail. There was no family history of similar cardiac disease, and hair and skin findings in the proband were not reported.
Rampazzo et al. (2002) reported on a genome scan in an Italian family in which the disorder appeared unlinked to any of the previously reported ARVD loci. Significantly positive linkage was detected for several markers on the short arm of chromosome 6 (maximum lod = 4.32 at theta = 0 for marker D6S309). All patients in the family shared a common haplotype. Since the novel 6p24 locus described by Rampazzo et al. (2002) was the eighth reported for ARVD, they named the locus ARVD8. Penetrance was approximately 50%.
ARVD8 is probably an infrequent form of ARVD, at least in northeast Italy; among 16 families in which Rampazzo et al. (2002) firmly established linkage with ARVD loci, this was the only family linked to 6p.
In affected members of an Italian family with ARVD mapping to 6p, Rampazzo et al. (2002) identified heterozygosity for a missense mutation in the desmoplakin gene (S299R; 125647.0003). They focused on the DSP gene because a homozygous DSP nonsense mutation had been reported to cause a biventricular dilated cardiomyopathy associated with keratoderma and woolly hair (605676) in an Ecuadorian family.
Rampazzo et al. (2002) noted that the involvement of DSP and JUP (173325) in 2 different ARVD clinical phenotypes, ARVD8 and Naxos disease (601214), suggests that some ARVDs may result from defects in intercellular connections.
Yang et al. (2006) analyzed 66 probands with ARVD and identified heterozygosity for variants in the DSP gene in 4 patients (see, e.g., R2834H, 125647.0012).
In a cohort of 65 patients with ARVD, Christensen et al. (2010) screened 5 desmosomal genes as well as the TGFB3 gene (190230) and identified 1 patient (family L) who was heterozygous for a splice site mutation in the DSP gene (125647.0024). This splice site mutation had previously been identified in a family with striate palmoplantar keratoderma (see PPKS2, 612908). From the same ARVD cohort, Christensen et al. (2010) also identified a patient from a consanguineous Danish family (family H) who was homozygous for a missense mutation in DSP and exhibited palmar keratoderma in addition to cardiac abnormalities.
Christensen, A. H., Benn, M., Bundgaard, H., Tybjaerg-Hansen, A., Haunso, S., Svendsen, J. H. Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. J. Med. Genet. 47: 736-744, 2010. [PubMed: 20864495] [Full Text: https://doi.org/10.1136/jmg.2010.077891]
Rampazzo, A., Nava, A., Malacrida, S., Beffagna, G., Bauce, B., Rossi, V., Zimbello, R., Simionati, B., Basso, C., Thiene, G., Towbin, J. A., Danieli, G. A. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 71: 1200-1206, 2002. [PubMed: 12373648] [Full Text: https://doi.org/10.1086/344208]
Yang, Z., Bowles, N. E., Scherer, S. E., Taylor, M. D., Kearney, D. L., Ge, S., Nadvoretskiy, V. V., DeFreitas, G., Carabello, B., Brandon, L. I., Godsel, L. M., Green, K. J., Saffitz, J. E., Li, H., Danieli, G. A., Calkins, H., Marcus, F., Towbin, J. A. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ. Res. 99: 646-655, 2006. [PubMed: 16917092] [Full Text: https://doi.org/10.1161/01.RES.0000241482.19382.c6]