SCIENTIFIC BACKGROUND

DSC2, DSG2, DSP, JUP, LMNA, PKP2, TGFB3, TMEM43

Arrythmogenic right ventricular cardiomyopathy (ARVC) is a mostly autosomal dominant inherited disease of the heart muscle in which the myocardium is progressively replaced by fatty and connective tissue. The connective tissue remodeling, which mainly affects the right ventricle, initially leads to a disturbance of the stimulus conduction with ventricular arrythmias, palpitations or syncope. The ECG typically shows epsilon waves and an inverted T-wave with broadened QRS complex in right precordial recording.

 

The arrythmias that can lead to sudden cardiac death are usually triggered by physical exertion. About one third of the index patients die suddenly between the ages of 14-20 years and this age seems to be a vulnerable period for fatal arrythmias. However, half of the carriers do not develop clinical symptoms until over 50 years of age and about one third do not become ill until old age. The frequency of ARVC is estimated at 1:5,000, and about half of the cases show a familial clustering. More than ten different forms of ARVC have now been documented.

 

The most common forms are caused by variants in genes that code for components of the desmosomes (cell-cell connections). Molecular genetic analysis of the genes that encode desmoplakine (DSP), plakophilin-2 (PKP2) and desmoglein-2 (DSG2) reveals variants in about 50-60% of patients. In about 5% of cases, the hereditary form of ARVC is caused by variants of other desmosomal protein genes such as plakoglobin (JUP) and desmocollin-2 (DSC2), as well as other genes such as transmembrane protein 43 (TMEM43) and transforming growth factor beta-3 (TGFB3). To date, no genetic cause can be proven in about 40% of ARVC cases.

 

References

Hall et al. 2018, Eur J Hum Genet doi.org/10.1038/s41431-018-0169- 4 / Walsh et al. 2017, Genet Med 19:192 / Medeiros-Domingo et al. 2016, Europace pii: euw098 / Bhonsale et al. 2015, Eur Heart J epub Jan / Schulze-Bahr et al. 2015, Kardiologe DOI 10.1007/s12181-014-0636-2 / Campuzano et al. 2013, J Med Genet 50:280 / Quarta et al. 2011, Circulation 123:2701 / Ackerman et al. 2011, Europace 13:1077

GENES
DSC2, DSG2, DSP, JUP, LMNA, PKP2, TGFB3, TMEM43
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