title: Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?
abstract: OBJECTIVE
  Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported missense mutations may not be pathogenic.
  
  
  METHODS
  We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing.
  
  
  RESULTS
  Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146-2A>T), 1 non-sense (R79X) and 4 missense mutations (Q62K in 2 patients, G489R, G673V) of undeterminable pathogeneity. None of these mutations was present in 650 controls. Five of the mutations were novel. Seven patients carried reported missense mutations (D26N, S140F, V587I); however, these mutations were identified in our healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in PKP2 showed unclear pathogeneity of several reported mutations.
  
  
  CONCLUSIONS
  Fifteen percent of Danish ARVC/D patients carried PKP2 mutations. Our finding of reported disease-causing mutations at a low frequency among healthy controls suggests that these variants are disease modifying but not directly disease causing. We recommend conservative interpretation of missense variants in PKP2, functional characterization and large-scale sequencing to clarify normal variation in the gene.
authors: Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors: Alex Hørby
authors: AH
authors: Christensen
authors: Marianne
authors: M
authors: Benn
authors: Anne
authors: A
authors: Tybjaerg-Hansen
authors: Stig
authors: S
authors: Haunso
authors: Jesper Hastrup
authors: JH
authors: Svendsen
mesh_terms: D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D016022:Case-Control Studies; D017124:Conserved Sequence; D003718:Denmark; D019143:Evolution, Molecular; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D051191:Plakophilins / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: C495337:PKP2 protein, human; D051191:Plakophilins