New Insight into the Variable Expression of Arrhythmogenic Right Ventricular Cardiomyopathy Provided by the Analysis of a Plakophilin-2 Splice Mutation

Dutch families. A founder effect was identified by haplotype sharing tests. This variant was associated with aberrant PKP2 splicing, demonstrated through transcriptional analysis. They identified ten additional mutation carriers in relatives, which were predominantly asymptomatic. Only four (40%) displayed a definite diagnosis of ARVC according to the Task Force Criteria, one (10%) had a borderline diagnosis and four (40%) displayed a normal phenotype (all women), confirming the reduced penetrance associated with this PKP2 mutation. Incomplete penetrance of desmosomal mutations partly explains why almost 50% of ARVC are apparently sporadic and has important consequences for the familial management of ARVC. Thus, a negative clinical evaluation does not exclude the possibility that a relative can be an asymptomatic mutation carrier, highlighting the usefulness of predictive genetic screening in this cardiomyopathy. The identification of such asymptomatic carriers is highly important to assess their arrhythmic risk and to set up an adequate preventive strategy and cardiac followup. In addition, asymptomatic mutation carriers can transmit the causative mutation to their offspring that can further develop a more severe phenotype and arrhythmic complications. In absence of a positive genetic Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mostly caused by heterozygous desmosomal gene mutations. Plakophilin 2 (PKP2) is the major disease-causing gene, accounting for 50–90% of mutation-positive patients [1, 2] . Nevertheless, the genetic cause remains unknown in half of the affected families [1] . The identification of genetic causes of ARVC has significantly improved the familial management of patients and has changed our perception of the natural history of the disease. Although probands usually display a severe phenotype with a high rate of ventricular arrhythmias, ARVC is often associated with mild presentation in relatives, suggesting that only a minority of mutation carriers develop symptoms and complications. Familial studies have indeed clearly shown that desmosomal gene mutations are associated with reduced penetrance, as only 34–39% of the first-degree relatives carrying a mutation display a definite diagnosis of ARVC based on the 2010 International Task Force Criteria [2–4] . In the latest issue of Cardiology, van der Smagt et al. [5] provide additional evidence of reduced penetrance associated with PKP2 mutations. They performed a large clinical familial analysis of a frequent heterozygous splicesite mutation (c.2489+4A 1 C) identified in four different Received: October 4, 2012 Accepted: October 4, 2012 Published online: November 23, 2012