The importance of variant reinterpretation in inherited cardiovascular diseases: Establishing the optimal timeframe

• Published in: PloS one 2024-05, Vol.19 (5), p.e0297914-e0297914
• Main Authors: Fernandez-Falgueras, Anna, Coll, Monica, Iglesias, Anna, Tiron, Coloma, Campuzano, Oscar, Brugada, Ramon
• Format: Article
• Language: English
• Subjects: Agreements; Analysis; Biology and Life Sciences; Brugada Syndrome - diagnosis; Brugada Syndrome - genetics; Cardiomyopathies - diagnosis; Cardiomyopathies - genetics; Cardiomyopathy; Cardiovascular diseases; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - genetics; Channelopathies - diagnosis; Channelopathies - genetics; Classification; Communication; Coronary artery disease; Diagnostic systems; Dilated cardiomyopathy; Disease; Genes; Genetic analysis; Genetic aspects; Genetic diversity; Genetic screening; Genetic Testing - methods; Genetic variance; Genetic Variation; Genomics; Heart diseases; Humans; Kappa coefficient; Long QT syndrome; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Medicine and Health Sciences; Patients; Periodicity; Prevention; Reclassification; Risk factors; Software; Tachycardia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0297914

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.