Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes
Por:
Martínez-Barrios E, Sarquella-Brugada G, Pérez-Serra A, Fernández-Falgueras A, César-Díaz S, Coll M, Puigmulé M, Iglesias A, Alcalde M, Vallverdú-Prats M, Ferrer-Costa C, Del Olmo B, Picó F, López L, Fiol JV, Cruzalegui JC, Hernández-Cera C, Arbelo E, Grassi S, Oliva A, Toro R, Brugada-Terradellas J, Brugada R and Campuzano O
Publicada:
1 feb 2022
Ahead of Print:
8 feb 2022
Categoría:
Medicine (miscellaneous)
Resumen:
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.
Filiaciones:
Martínez-Barrios E:
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain
Sarquella-Brugada G:
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain
Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
Pérez-Serra A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Fernández-Falgueras A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Cardiology Service, Hospital Josep Trueta, University of Girona, 17007 Girona, Spain
César-Díaz S:
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain
Coll M:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Puigmulé M:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Iglesias A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Alcalde M:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Vallverdú-Prats M:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Ferrer-Costa C:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Del Olmo B:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Picó F:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
López L:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Fiol JV:
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain
Cruzalegui JC:
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain
Hernández-Cera C:
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain
Arbelo E:
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036 Barcelona, Spain
Grassi S:
Institute of Public Health, Section Legal Medicine, Catholic University, 20123 Rome, Italy
Oliva A:
Institute of Public Health, Section Legal Medicine, Catholic University, 20123 Rome, Italy
Toro R:
Medicine Department, School of Medicine, University of Cadiz, 11003 Cadiz, Spain
Brugada-Terradellas J:
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036 Barcelona, Spain
Brugada R:
Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Cardiology Service, Hospital Josep Trueta, University of Girona, 17007 Girona, Spain
Campuzano O:
Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
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