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Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria


Costa, Sarah; Medeiros-Domingo, Argelia; Gasperetti, Alessio; Akdis, Deniz; Berger, Wolfgang; James, Cynthia A; Ruschitzka, Frank; Brunckhorst, Corinna; Duru, Firat; Saguner, Ardan M (2020). Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria. Circulation: Genomic and Precision Medicine, 14(1):e003047.

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 (ACMG) criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria (TFC) was reclassified after genetic re-adjudication. 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 to other genes (PKP2, n=1, 8.3%; desmosomal non-PKP2, n=20, 66.7%; non-desmosomal, n=26, 68.4%) (p=0.001 for overall comparison; PKP2 vs desmosomal non-PKP2, p=0.001; PKP2 vs non-desmosomal, 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%) of 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.

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 (ACMG) criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria (TFC) was reclassified after genetic re-adjudication. 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 to other genes (PKP2, n=1, 8.3%; desmosomal non-PKP2, n=20, 66.7%; non-desmosomal, n=26, 68.4%) (p=0.001 for overall comparison; PKP2 vs desmosomal non-PKP2, p=0.001; PKP2 vs non-desmosomal, 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%) of 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
04 Faculty of Medicine > Institute of Medical Molecular Genetics
Dewey Decimal Classification:610 Medicine & health
Language:German
Date:24 November 2020
Deposited On:17 Feb 2021 09:27
Last Modified:17 Feb 2021 09:30
Publisher:American Heart Association
ISSN:2574-8300
OA Status:Closed
Publisher DOI:https://doi.org/10.1161/CIRCGEN.120.003047
PubMed ID:33232181

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