The phospholamban p.Arg14del founder mutation in Dutch patients with arrhythmogenic cardiomyopathy

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is considered a hereditary cardiac disease, characterised by ventricular arrhythmias with left bundle branch block morphology, fibro-fatty replacement of cardiomyocytes and predominantly affecting the right ven-tricle [1, 2]. Recently, arrhythmogenic cardiomyopathy (AC) was suggested as the preferred terminology [3]. The most important considerations for this are that patients and families with ventricular arrhythmia and similar ARVD/C histopathological changes in the left ventricle have been recognised and described as left-dominant arrhythmogenic cardiomyopathy [4]. Mutations in desmosomal genes are associated with both ARVD/C and left-dominant arrhythmogenic cardiomyopathy and at the molecular level both ventricles and the interventricular septum are similarly affected [5, 6]. Classically AC is considered a disease of the desmo-somes. Desmosomes are protein complexes located in the intercalated disk, important for mechanical integrity. For example, in approximately 60 % of Dutch AC patients a pathogenic desmosomal mutation is found, predominantly in the PKP2 gene [7]. Non-desmosomal genes have also been identified in families with phenotypical AC, for example TMEM43 [8]. Another mutation in a non-desmosomal gene is the p.Arg14del mutation in the phospholamban (PLN) gene. Phospholamban is involved in calcium homeo-stasis in the sacroplasmatic reticulum of the cardiac muscle cell [9]. Mutation carriers are phenotypically characterised by low-voltage electrocardiograms, ventricular arrhythmias, and contractile dysfunction involving both ventricles. Van der Zwaag et al. found that the PLN mutation was especially prevalent in the Netherlands, both in dilated car-diomyopathy (13 %) as well as in AC (12 %) [10]. This was a surprising finding because in other cohorts the prevalence of the PLN p.Arg14del mutation was found to be very low, between 0.08 % and 0.38 % [11]. In this issue of the Journal, Van der Zwaag et al. describe the origin of the PLN p.Arg14del founder mutation in the Netherlands [11]. This paper fits nicely in a series of articles started in 2009 on founder mutations in the Netherlands in different cardiomy-opathies [12]. Founder mutations are mutations that emerged in a population many generations ago and have subsequently spread among following generations. In the study by Van der Zwaag et al. [11]. a large number of PLN p.Arg14del founder mutation carriers (probands and family members) were identified, in total 459 individuals. The authors analysed the origin of the PLN founder mutation first by haplotype analysis revealing that the mutation is estimated to be between 575 and 825 years old. Subsequently , in order to approximate the …