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Title: | Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes |
Author: | Martínez Barrios, Estefanía Sarquella Brugada, Georgia Pérez Serra, Alexandra Fernández Falgueras, Anna César, Sergi Coll, Mònica Puigmulé Raurich, Marta Iglesias, Anna Alcalde, Mireia Vallverdú Prats, Marta Ferrer Costa, Carles Olmo, Bernat del Picó, Ferran López, Laura Fiol, Victoria Cruzalegui, José Hernández Cera, Clara Arbelo, Elena Grassi, Simone Oliva, Antonio Toro, Rocío Brugada Terradellas, Josep, 1958- Brugada, Ramon Campuzano, Òscar |
Keywords: | Arrítmia Genètica Arrhythmia Genetics |
Issue Date: | 8-Feb-2022 |
Publisher: | MDPI |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/jpm12020241 |
It is part of: | Journal of Personalized Medicine, 2022, vol. 12, num. 2, |
URI: | http://hdl.handle.net/2445/199558 |
Related resource: | https://doi.org/10.3390/jpm12020241 |
ISSN: | 2075-4426 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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Discerning the Ambiguous Role of Missense TTN Variants in_PersonalizedMedicine.pdf | 5.09 MB | Adobe PDF | View/Open |
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