Sarah Costa1, Argelia Medeiros-Domingo2, Alessio Gasperetti1, Deniz Akdis1, Wolfgang Berger3, Cynthia A James4, Frank Ruschitzka1, Corinna B Brunckhorst1, Firat Duru1,5, Ardan M Saguner1. 1. Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Switzerland (S.C., A.G., D.A., F.R., C.B.B., F.D., A.M.S.). 2. Swiss DNAlysis, Dubendorf, Switzerland (A.M.-D.). 3. Institute of Molecular Genetics, University of Zurich, Schlieren, Switzerland (W.B.). 4. Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (C.A.J.). 5. Zurich Center for Integrative Human Physiology (ZIHP), Switzerland (W.B., F.D.).
Abstract
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis. METHODS: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication. RESULTS: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 (PKP2) were shown to reclassify less frequently as compared with other genes (PKP2, n=1, 8.3%; desmosomal non-PKP2, n=20, 66.7%; nondesmosomal, n=26, 68.4%; P=0.001for overall comparison; PKP2 versus desmosomal non-PKP2, P=0.001; PKP2 versus nondesmosomal, P<0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants. CONCLUSIONS: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis. METHODS: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication. RESULTS: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 (PKP2) were shown to reclassify less frequently as compared with other genes (PKP2, n=1, 8.3%; desmosomal non-PKP2, n=20, 66.7%; nondesmosomal, n=26, 68.4%; P=0.001for overall comparison; PKP2 versus desmosomal non-PKP2, P=0.001; PKP2 versus nondesmosomal, P<0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants. CONCLUSIONS: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.
Authors: Elena Zaklyazminskaya; Margarita Polyak; Anna Shestak; Mariam Sadekova; Vera Komoliatova; Irina Kiseleva; Leonid Makarov; Dmitriy Podolyak; Grigory Glukhov; Han Zhang; Denis Abramochkin; Olga S Sokolova Journal: Genes (Basel) Date: 2022-03-22 Impact factor: 4.141
Authors: Marta Vallverdú-Prats; Mireia Alcalde; Georgia Sarquella-Brugada; Sergi Cesar; Elena Arbelo; Anna Fernandez-Falgueras; Mónica Coll; Alexandra Pérez-Serra; Marta Puigmulé; Anna Iglesias; Victoria Fiol; Carles Ferrer-Costa; Bernat Del Olmo; Ferran Picó; Laura Lopez; Paloma Jordà; Ana García-Álvarez; Coloma Tirón de Llano; Rocío Toro; Simone Grassi; Antonio Oliva; Josep Brugada; Ramon Brugada; Oscar Campuzano Journal: J Pers Med Date: 2021-02-26