Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

Abstract

Background: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified throughout genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 post-mortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment. Funding Statement:This work was supported by Obra Social La Caixa Foundation (ID 100010434), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS, PI17/01690) from Instituto Salud Carlos III (ISCIII), Sociedad Espanola de Cardiologia (Proyecto Investigacion Basica Cardiologia 2015 de los Socios Estrategicos SEC), and “Fundacio Privada Daniel Bravo Andreu”. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: Genetic analysis was approved by the ethics committee of Hospital Josep Trueta (Girona, Spain) following the Helsinki II declaration. Written informed consent was obtained from all patients included in the study.