2026-04-05T12:52:01Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/1995582025-12-04T19:25:14Zcom_2072_1057col_2072_478858col_2072_478917
RECERCAT author Martínez Barrios, Estefanía author Sarquella Brugada, Georgia author Pérez Serra, Alexandra author Fernández Falgueras, Anna author César Diaz, Sergio author Coll, Mònica author Puigmulé Raurich, Marta author Iglesias, Anna author Alcalde, Mireia author Vallverdú Prats, Marta author Ferrer Costa, Carles author Olmo, Bernat del author Picó, Ferran author López, Laura author Fiol, Victoria author Cruzalegui, José author Hernández Cera, Clara author Arbelo, Elena author Grassi, Simone author Oliva, Antonio author Toro, Rocío author Brugada Terradellas, Josep, 1958- author Brugada, Ramon author Campuzano Larrea, Oscar 2023-06-21T10:36:52Z2023-06-21T10:36:52Z2022-02-082023-06-20T12:41:07Z The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine. cc by (c) Martínez Barrios, Estefanía et al, 2022 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Arrítmia Genètica Arrhythmia Genetics Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion