Abstract 1930: The ARVD/C Variome of the Netherlands
Background: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a disorder characterized by segmental fibro-fatty replacement of the right ventricular myocardium leading to electrical instability predisposing to ventricular arrhythmias and sudden cardiac death. In 30 –50% of cases the disease is familial with an autosomal dominant mode of inheritance with reduced penetrance and variable expression. The discovery of high yields of mutations in the PKP2 gene encoding a desmosomal protein, and mutations, with lower yields, in other desmosomal genes (DSG2, DSC2, DSP, DES and JUP), showed that ARVD/C is a desmosomal disease. In addition, a mutation in the TMEM43 gene, not (yet) related to the desmosome, was recently identified. Goal of this study was to evaluate the prevalence of mutations in all currently known ARVD/C-related genes in Dutch ARVC patients.
Methods: Using different genetic techniques (DHPLC, DGGE, direct sequencing), the PKP2, DSG2, DSC2, DSP, DES JUP and TMEM43 genes were and are currently studied in 57 patients fulfilling ARVC Task Force Criteria. In addition, a deep sequencing protocol to analyze these genes within one single experiment was initiated recently. To validate the applicability of this technique in a diagnostic setting, all ARVD/C related genes were also analyzed in these patients, using this deep sequencing protocol.
Results: 40% of our ARVD/C patients carry PKP2 mutations, 7% carry DSG2 mutations, 2% carry a mutation in DSC2, and 2% carry a mutation in both DSG2 and DSC2. Among the DSG2 and/or DSC2 mutation-positive probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. No mutations were identified in the TMEM43, DSP, JUP and DES genes, although a subset of the analyses is pending.
Conclusions: Mutations in DSG2 and DSC2 are together less prevalent (10%) than PKP2 mutations (40%) in Dutch ARVD/C patients. Interestingly, bi-allelic or digenic DSC2 and/or DSG2 mutations are frequently identified, suggesting that a single mutation is less likely to cause a full blown ARVD/C phenotype. These results will be integrated in our recently launched, freely accessible online database, providing updated information on mutations in ARVD/C-associated genes (www.arvcdatabase.info).