Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis
Por:
Martínez-Barrios E, Greco A, Cruzalegui JC, César-Díaz S, Nuria Díez Escuté, Patricia Cerralbo Martín, Chipa F, Zschaeck-Luzardo I, Fogaça-da-Mata M, Díez-López C, Arbelo E, Grassi S, Oliva A, Toro R, Sarquella-Brugada G and Campuzano O
Publicada:
1 nov 2024
Ahead of Print:
8 nov 2024
Resumen:
Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; however, it requires an accurate interpretation of the data to achieve a clinically actionable outcome. This is particularly challenging for the large number of rare variants obtained by current high-throughput techniques, which are mostly classified as of unknown significance. Methods: In this work, we present a new algorithm for the genetic interpretation of the remaining rare variants in order to shed light on their potential clinical implications and reduce the burden of unknown significance. Results: Our study illustrates the potential utility of our individualized comprehensive stepwise analyses focused on the rare variants associated with IAS, which are currently classified as ambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions: We advocate for personalized disease-focused population frequency data and family segregation analyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguity should not influence medical decisions, but a potential deleterious role would suggest a closer clinical follow-up and frequent genetic data review for a more personalized clinical approach.
Filiaciones:
Martínez-Barrios E:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Greco A:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Cruzalegui JC:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
César-Díaz S:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Nuria Díez Escuté:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Patricia Cerralbo Martín:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Zschaeck-Luzardo I:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Fogaça-da-Mata M:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Cardiology Unit, Hospital de Santa Cruz, Centro Hospitalar Lisboa Ocidental, 2790-134 Lisboa, Portugal
Díez-López C:
Cardiovascular Diseases Research Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Spain
Advanced Heart Failure and Heart Transplant Unit, Department of Cardiology, Bellvitge University Hospital, 08908 Hospitalet de Llobregat, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Arbelo E:
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
Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain
Institut d'Investigació August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain
Grassi S:
Department of Health Sciences, Section of Forensic Medical Sciences, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
Oliva A:
Department of Health Surveillance and Bioethics, Section of Legal Medicine, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Toro R:
Medicine Department, School of Medicine, University of Cadiz, 11003 Cadiz, Spain
Sarquella-Brugada G:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Pediatric Arrhythmias, Genetic Cardiology and Sudden Death, Cardiovascular Diseases in the Development, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 AZ Amsterdam, The Netherlands
Medical Science Department, School of Medicine, Universitat de Girona, 17003 Girona, Spain
:
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Medical Science Department, School of Medicine, Universitat de Girona, 17003 Girona, Spain
Institut d'Investigació Biomèdiques de Girona (IDIBGI), 17190 Salt, Spain
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