Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders

Abstract

Hereditary arrhythmogenic diseases represent a significant group of genetically based heart rhythm disorders that can lead to serious health consequences. Genetic diagnostics are crucial for identifying the underlying genetic variants responsible for these conditions. However, variants of uncertain significance (VUS) are often found, whose clinical relevance is unclear. These VUS pose a challenge for interpretation and therapeutic decision-making. The aim of this study was to re-evaluate rare genetic variants in patients with hereditary arrhythmogenic diseases to reduce the number of VUS, thereby improving risk stratification and personalized patient treatment. Genetic analysis was carried out as a part of genetic diagnostics. Samples from patients with clinical indications of a hereditary arrhythmogenic disease were analysed. The data were evaluated using databases and in silico prediction tools to ensure accurate variant classification. Classification followed the guidelines of the American College of Medical Genetics and Genomics (ACMG) and was reviewed by independent experts. In total, 53 VUS in 30 genes were identified and re-evaluated, with 17 variants (32%) being reclassified. Of these, 13% were classified as likely benign or benign, and 6% as likely pathogenic. The reclassification primarily involved variants initially classified between 2017 and 2019, with the reclassification rate during this period being 50% to 60%. The results of this study highlight the importance of regularly reclassifying VUS to reduce uncertainty in genetic diagnostics. Advances in science and technology enable a more precise assessment of the clinical relevance of genetic variants, leading to improved risk assessment and personalized treatment strategies for patients. Additionally, the findings contribute to expanding the knowledge base on the genetic principles or basis of hereditary arrhythmogenic diseases and promote the development of new diagnostic and therapeutic approaches. This study highlights the critical importance of continuously reviewing and reclassifying VUS to reduce uncertainties in genetic diagnostics. Accurate genetic diagnosis serves as basis for effective patient care and targeted therapeutic interventions. By improving diagnostic precision, the study significantly advances the understanding of hereditary arrhythmogenic diseases and lays the groundwork for personalized medical care. Additionally, it emphasizes the ongoing need for genetic data review while offering valuable insights for future research and clinical practice.