Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy
Por:
Pérez-Serra A, Toro R, Martínez-Barrios E, Iglesias A, Fernandez-Falgueras A, Alcalde M, Coll M, Puigmulé M, Del Olmo B, Picó F, Lopez L, Arbelo E, César-Díaz S, Llano CT, Mangas A, Brugada-Terradellas J, Sarquella-Brugada G, Brugada R and Campuzano O
Publicada:
1 abr 2024
Ahead of Print:
29 mar 2024
Resumen:
Dilated cardiomyopathy is a heterogeneous entity that leads to heart failure and malignant arrhythmias. Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy.
Filiaciones:
Pérez-Serra A:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Toro R:
Medicine Department, School of Medicine, Cadiz University, 11003 Cadiz, Spain
Research Unit, Biomedical Research and Innovation Institute of Cadiz (INiBICA), Puerta del Mar University Hospital, 11009 Cadiz, Spain
Martínez-Barrios E:
Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950 Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Iglesias A:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Fernandez-Falgueras A:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Cardiology Service, Hospital Josep Trueta, University of Girona, 17007 Girona, Spain
Alcalde M:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Coll M:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Puigmulé M:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Del Olmo B:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Picó F:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Lopez L:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Arbelo E:
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036 Barcelona, Spain
César-Díaz S:
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950 Barcelona, Spain
Llano CT:
Cardiology Service, Hospital Josep Trueta, University of Girona, 17007 Girona, Spain
Mangas A:
Medicine Department, School of Medicine, Cadiz University, 11003 Cadiz, Spain
Research Unit, Biomedical Research and Innovation Institute of Cadiz (INiBICA), Puerta del Mar University Hospital, 11009 Cadiz, Spain
Internal Medicine Department, Puerta del Mar University Hospital, School of Medicine, University of Cadiz, 11009 Cadiz, Spain
Brugada-Terradellas J:
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036 Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Sarquella-Brugada G:
Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950 Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Brugada R:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Cardiology Service, Hospital Josep Trueta, University of Girona, 17007 Girona, Spain
Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
Campuzano O:
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain
Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
Green Submitted, gold
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