Why the study?
Interpretation of genetic test results in ARVC can be challenging, warranting systematic reclassification of variants to assess the impact on ARVC diagnosis.
Does genetic variant reassessment using 2015 ACMG criteria impact the diagnosis of ARVC based on 2010 Task Force Criteria in patients with a putative disease-causing genetic variant?
Does genetic variant reassessment using 2015 ACMG criteria impact the diagnosis of ARVC based on 2010 Task Force Criteria in patients with a putative disease-causing genetic variant?
Reassessment of genetic variants using updated ACMG criteria frequently leads to reclassification, significantly impacting the clinical diagnosis of ARVC and highlighting the need for accurate variant pathogenicity determination.
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May prompt ARVC diagnostic downgrades; leaves open need for prospective validation of ACMG reassessment in cardiomyopathy.
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.
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Medeiros‐Domingo et al. (2020) studied this question.
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