Journal article
Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria
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Costa, Sarah
ORCID
Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
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Medeiros-Domingo, Argelia
Swiss DNAlysis, Dubendorf, Switzerland
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Gasperetti, Alessio
ORCID
Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
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Akdis, Deniz
Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
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Berger, Wolfgang
Institute of Molecular Genetics, University of Zurich, Schlieren, Switzerland
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James, Cynthia A.
ORCID
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD
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Ruschitzka, Frank
Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
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Brunckhorst, Corinna
Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
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Duru, Firat
ORCID
Department of Cardiology, University Heart Center Zurich & Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
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Saguner, Ardan M.
ORCID
Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
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Published in:
- Circulation: Genomic and Precision Medicine. - Ovid Technologies (Wolters Kluwer Health). - 2020
English
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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Language
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Open access status
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closed
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Identifiers
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Persistent URL
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https://sonar.ch/global/documents/167588
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