OBJECTIVES: 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.
OBJECTIVES: 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: Mireia Alcalde; Oscar Campuzano; Georgia Sarquella-Brugada; Elena Arbelo; Catarina Allegue; Sara Partemi; Anna Iglesias; Antonio Oliva; Josep Brugada; Ramon Brugada Journal: Clin Res Cardiol Date: 2014-11-15 Impact factor: 5.460
Authors: Jamie D Kapplinger; Andrew P Landstrom; Benjamin A Salisbury; Thomas E Callis; Guido D Pollevick; David J Tester; Moniek G P J Cox; Zahir Bhuiyan; Hennie Bikker; Ans C P Wiesfeld; Richard N W Hauer; J Peter van Tintelen; Jan D H Jongbloed; Hugh Calkins; Daniel P Judge; Arthur A M Wilde; Michael J Ackerman Journal: J Am Coll Cardiol Date: 2011-06-07 Impact factor: 24.094