RT journal article
T1 Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes
A1 Martínez-Barrios, Estefanía
A1 Sarquella-Brugada, Georgia
A1 Perez-Serra, Alexandra
A1 Fernandez-Falgueras, Anna
A1 Cesar, Sergi
A1 Coll, Mónica
A1 Puigmulé, Marta
A1 Iglesias, Anna
A1 Alcalde, Mireia
A1 Vallverdú-Prats, Marta
A1 Ferrer-Costa, Carles
A1 del Olmo, Bernat
A1 Picó, Ferran
A1 Lopez, Laura
A1 Fiol, Victoria
A1 Cruzalegui, José
A1 Hernández, Clara
A1 Arbelo, Elena
A1 Grassi, Simone
A1 Oliva, Antonio
A1 Toro Cebada, Rocío
A1 Brugada, Josep
A1 Brugada, Ramón
A1 Campuzano, Oscar
A2 Medicina
K1 sudden cardiac death
K1 inherited arrhythmogenic syndromes
K1 TTN
K1 genetics
K1 interpretation
AB 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.
PB MDPI
SN 2075-4426
YR 2022
FD 2022-02
LK http://hdl.handle.net/10498/26817
UL http://hdl.handle.net/10498/26817
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 07-nov-2026