TY - JOUR
T1 - Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria
AU - Costa, Sarah
AU - Medeiros-Domingo, Argelia
AU - Gasperetti, Alessio
AU - Akdis, Deniz
AU - Berger, Wolfgang
AU - James, Cynthia A.
AU - Ruschitzka, Frank
AU - Brunckhorst, Corinna B.
AU - Duru, Firat
AU - Saguner, Ardan M.
N1 - Funding Information:
The Zurich ARVC Program is supported by grants from the Georg and Bertha Schwyzer-Winiker Foundation, the Baugarten Foundation, the Leone-Wild Charitable Foundation, the Swiss Heart Foundation, and the Swiss National Science Foundation.
Funding Information:
Dr Saguner reports educational grants from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Medtronic, and Pfizer-BMS outside this work. He owns stock from Gilead Sciences. The other authors report no conflicts. Dr James is reports a research grant by Boston Scientific Corp. Dr Medeiros is the founder of Swiss DNAlysis. r Ruschitzka has not received personal payments by pharmaceutical companies or device manufacturers in the last three years (remuneration for the time spent in activities, such as participation in steering committee member of clinical trials, were made directly to the University of Zurich). The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research-, educational-and/or travel grants from Abbott, Am-gen, Astra Zeneca, Bayer, B. Braun, Biosense Webster, Biosensors Europe AG, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, Cardinal Health Switzerland, Daiichi, Diatools AG, Edwards Lifesciences, Guidant Europe NV (BS), Hamilton Health Sciences, Kaneka Corporation, Labormedizinisches Zentrum, Medtronic, MSD, Mundipharma Medical Company, Novartis, Novo Nordisk, Orion, Pfizer, Quintiles Switzerland Sarl, Sanofi, Sarstedt AG, Servier, SIS Medical, SSS International Clinical Research, Terumo Deutschland, V-Wave, Vascular Medical, Vifor, Wissens Plus, ZOLL. The research and educational grants do not impact on Prof. Ruschitzka`s personal remuneration.
Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - cardiomyopathy
KW - diagnosis
KW - genetic testing
KW - plakophilin
KW - registry
UR - http://www.scopus.com/inward/record.url?scp=85102211409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102211409&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.120.003047
DO - 10.1161/CIRCGEN.120.003047
M3 - Article
C2 - 33232181
AN - SCOPUS:85102211409
SN - 1942-325X
VL - 14
SP - E003047
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 1
ER -