Update on rare variants in inherited arrhythmogenic syndromes: when to reclassify?

Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Background Discerning a definite pathogenic role of rare variants in genes associated with inherited arrhythmogenic syndromes (IAS) is critical because of their potential implications for clinical decision-making. The discovery of new gene-disease associations, the publication of functional studies and update on population genetic data may lead to changes in the interpretation of genetic variants classified in previous studies. Aim To update the classification of rare variants previously identified in genetic testing of IAS cases. Methods This is a retrospective descriptive analysis that enrolled rare variants previously identified in genetic tests from 145 families with a clinical diagnosis of any IAS between 2015-2020. These variants were re-evaluated and reclassified following the American College of Medical Genetics and Genomics guidelines, including newly available data. Results In their previous study, 78% of all cases harboured a rare variant classified as a variant of uncertain significance (VUS). Only 22% had a definitive diagnosis with a variant classified as pathogenic (P) or likely pathogenic (LP). In our comprehensive reanalysis following current available data, the classification of 26.7% of these variants changed, mainly due to updated population frequencies, but also to the addition of clinical data and segregation studies. As showed in 2015, the majority of variants were now classified as VUS (57.5%). The percentage of rare variants classified as potentially deleterious increased from 22% to 30%. In addition, 76.5% of reclassified variants gained certainty. Conclusions The large number of variants remaining as VUS is one of the main limitations in current diagnosis of IAS. Clarifying the role of rare variants can help to obtain a definitive genetic diagnosis, allowing the identification of those carriers at risk of developing the disease and ruling out those who are not. We propose that a periodic review of rare variants no later than 5 tears may help to improve clinical decision-making in the diagnosis, follow-up, treatment and risk stratification of families with IAS.