Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the Arrhythmogenic Right Ventricular Cardiomyopathy Registry of South Africa

Arrhythmogenic Right Ventricular Cardiomyopathy

“…A significant proportion of the alleles identified are of low pathogenicity, because many family members carrying a single mutation do not meet the Task Force criteria. Compound heterozygous mutations or digenic mutations are not so rarely found [27][28][29] as to support the concept of a gene-dose effect in determining the disease phenotype. This is quite evident in the recessive cardiocutaneous syndromes, which are characterized by an earlier clinical onset of cardiac involvement with a higher penetrance of complications than the autosomal-dominant form.…”

“…[21][22][23][24] Founder mutations effects, geographic differences in either genetic or nongenetic factors, different definitions of mutation pathogenicity, and various diagnostic criteria adopted are the main factors that could explain the variable prevalence of pathogenic mutations among ARVC populations. [25][26][27][28][29][30][31][32] Recent data coming from large series of familial ARVC demonstrate that up to 70% of index cases present a causal/ possibly causal desmosomal gene mutation. 31 The majority of mutations involve PKP2 and DSG2, followed by DSP and DCS2.…”

“…The overall incidence of cardiac arrest attributable to VF varies among different series, 27,43,[51][52][53][54][55][56][57][58][59][60][61] ranging from a low mortality rate in familial forms during a mean follow-up of 8.5 years (0.08% per year in the series by Nava et al 43 ) to high mortality rate mostly attributable to SCD during a mean follow-up of 4.6 years (3.6% per year, in the series by Lemola et al 58 ) (Table 2).…”

Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy

“…Loss-of-function mutations in five different desmosomal protein encoding genes, plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP), have been identified in AC [6]. The prevalence of these mutations might be related to ethnicity, founder mutations or founder populations [7][8][9] and therefore may be different in geographically distinct populations. For example, as shown by Van der Zwaag et al [9] 12 index patients carrying the same PKP2 mutation shared the same haplotype, indicative for a common founder.…”

Plakophilin 2A is the dominant isoform in human heart tissue: consequences for the genetic screening of arrhythmogenic right ventricular cardiomyopathy

“…However, the relative expression, the tissue specificity and the role of both isoforms are still unknown, especially in the heart and in ARVC. Recently, four mutations located in the alternatively spliced exon 6 have been reported: the p.Gly489Arg (c.1465 G→A) missense variant identified twice,17 18 the p.Arg490Trp (c.1468 C→T) and the splice variant c.1379[-]1G→A (http://www.arvcdatabase.info). Although those variants have been classified as causal mutations based on their absence in control populations by some authors,18 their pathogenicity has been questioned by others15 17 and still needs to be ascertained.…”