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

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.

A Novel Diagnostic Score Integrating Atrial Dimensions to Differentiate between the Athlete’s Heart and Arrhythmogenic Right Ventricular Cardiomyopathy

“…The fifth category (ventricular arrhythmias) is also often inconclusive since some patients do not present with ventricular tachycardia or ventricular tachycardia morphology has not been captured by 12-lead ECG. The sixth category (family history and genetic testing) can also be difficult to assess, given the fact that ARVC does not follow a familial pattern in up to 50% of cases, genetic test results are prone to misinterpretation, and desmosomal variants have also been identified in both a healthy population and athletes [ 17 , 18 ].…”

Pregnancy in arrhythmogenic cardiomyopathy

“…The detection of a genetic mutation or variant supports, but does not necessarily prove, a causative relation to penetrance, manifestation, expression, and severity of AC. Therefore, to draw any clinically relevant conclusions, positive genetic findings always require confirmation and evidence that the detected genetic variant is indeed pathogenic for AC [ 20 ]. Expert interpretation of gene–disease associations and variant pathogenicity is supported by the Clinical Genome (ClinGen) Resource Cardiovascular Working Group ( https://clinicalgenome.org ; [ 41 , 45 , 49 , 60 ]).…”

“…Expert interpretation of gene–disease associations and variant pathogenicity is supported by the Clinical Genome (ClinGen) Resource Cardiovascular Working Group ( https://clinicalgenome.org ; [ 41 , 45 , 49 , 60 ]). To determine the likelihood of pathogenicity of a genetic variant and its relation to disease, the following classification has been proposed: pathogenic (class 5: >95%), likely pathogenic (class 4: >90%), variant of uncertain significance = VUS (class 3: 10–90%), likely benign (class 2: <10%), and benign (class 1: <5%) [ 8 , 20 , 49 , 60 , 62 ].…”

Genetics of Cardiomyopathy: Clinical and Mechanistic Implications for Heart Failure

“…Unlike all other forms of cardiomyopathy, the diagnostic criteria for ARVC include the presence of a pathogenic variant in genes associated with ARVC as the major diagnostic criteria. 152) However, it has not been determined which variants have sufficient evidence to be considered as disease-causing; therefore, it may be challenging to define the pathogenicity to a variant. In addition, a negative genetic test does not rule out the possibility that the phenotype is due to a variant in an unknown gene or that the molecular genetic screening technique cannot detect all disease-causing variants, including large deletions or duplications.…”

“…The electrical and structural abnormalities found on CMR in ARVC genetic variant carriers identified those who are at risk for arrhythmic events and may benefit from ICD implantation. 152) 161) …”