Reinterpretation of genetic testing for Cardiomyopathies: Less is more

Abstract Background In the last years, the concept of reinterpretation of genetic testing has been considered as part of the diagnostic workflow. However, this process requires time, expert curators and new pieces of evidence to evaluate, as functional studies, segregation and allele frequency data. Last year, the European Society of Cardiology (ESC) published new guidelines for the management of cardiomyopathies. This document includes a precise list of genes associated with the different types of Cardiomyopathies and their level of contribution, according to ClinGen evaluation: definitive/strong, moderate, limited, and refuted/disputed. This document poses a real support in the reinterpretation of tests that report variants in genes not clearly correlated with these phenotypes. Purpose To evaluate the impact of the new ESC indications regarding genetic testing, we reconsidered all genetic results performed in our Clinic in patients with confirmed or suspicious Cardiomyopathy. Methods From 2017 to 2023 we analyzed 296 probands eligible for Cardiomyopathy genetic testing, in particular: 105 patients were tested for Arrhythmogenic Cardiomyopathy (ACM), 113 for Hypertrophic Cardiomyopathy (HCM) and 78 for Dilated Cardiomyopathy (DCM), using a custom sequencing panel including 44 genes (11 genes for ACM, 34 for DCM and 29 for HCM). Results Comparison analysis with the genes reported from the ESC guidelines, considering only the definitive, moderate, and strong genes, showed that 24 genes are not more associated with the phenotype and then not clinically actionable. In this scenario, we reconsidered 12 variants (8%), previously classified as VUS, changing the referral status of 8 patients, from uncertain to negative. Conclusions These results highlight the importance of variant reinterpretation as a fundamental step of genetic testing, posing the importance of the selection of the genes to analyze, in order to improve the management of the patients.