Reevaluation of ambiguous genetic variants in sudden unexplained deaths of a young cohort
Por:
Martínez-Barrios E, Sarquella-Brugada G, Perez-Serra A, Fernandez-Falgueras A, César-Díaz S, Alcalde M, Coll M, Puigmulé M, Iglesias A, Ferrer-Costa C, Del Olmo B, Picó F, Lopez L, Fiol JV, Cruzalegui JC, Hernández-Cera C, Arbelo E, Díez-Escuté N, Cerralbo P, Grassi S, Oliva A, Toro R, Brugada-Terradellas J, Brugada R and Campuzano O
Publicada:
1 mar 2023
Ahead of Print:
1 ene 2023
Categoría:
Pathology and forensic medicine
Resumen:
Sudden death cases in the young population remain without a conclusive cause of decease in almost 40% of cases. In these situations, cardiac arrhythmia of genetic origin is suspected as the most plausible cause of death. Molecular autopsy may reveal a genetic defect in up to 20% of families. Most than 80% of rare variants remain classified with an ambiguous role, impeding a useful clinical translation. Our aim was to update rare variants originally classified as of unknown significance to clarify their role. Our cohort included fifty-one post-mortem samples of young cases who died suddenly and without a definite cause of death. Five years ago, molecular autopsy identified at least one rare genetic alteration classified then as ambiguous following the American College of Medical Genetics and Genomics' recommendations. We have reclassified the same rare variants including novel data. About 10% of ambiguous variants change to benign/likely benign mainly because of improved population frequencies. Excluding cases who died before one year of age, almost 21% of rare ambiguous variants change to benign/likely benign. This fact makes it important to discard these rare variants as a cause of sudden unexplained death, avoiding anxiety in relatives' carriers. Twenty-five percent of the remaining variants show a tendency to suspicious deleterious role, highlighting clinical follow-up of carriers. Periodical reclassification of rare variants originally classified as ambiguous is crucial, at least updating frequencies every 5 years. This action aids to increase accuracy to enable and conclude a cause of death as well as translation into the clinic.
Filiaciones:
Martínez-Barrios E:
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, 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
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Sarquella-Brugada G:
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Esplugues de Llobregat, 08950, Barcelona, Spain
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950, Barcelona, Spain
Medical Science Department, School of Medicine, University of Girona, 17003, Girona, Spain
Perez-Serra A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190, Girona, Spain
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain
Fernandez-Falgueras A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190, Girona, Spain
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain
César-Díaz S:
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950, Barcelona, Spain
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Esplugues de Llobregat, 08950, Barcelona, 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
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
Ferrer-Costa C:
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190, Girona, Spain
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, 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
Lopez 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:
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, 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
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Cruzalegui JC:
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950, Barcelona, Spain
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Esplugues de Llobregat, 08950, Barcelona, Spain
Hernández-Cera C:
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, 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
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Arbelo E:
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036, Barcelona, Spain
Díez-Escuté N:
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, 08036, Barcelona, Spain
Cerralbo P:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950, Barcelona, Spain
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Esplugues de Llobregat, 08950, Barcelona, Spain
Grassi S:
Department of Health Sciences, Section of Forensic Medical Sciences, University of Florence, largo Brambilla 3, 50134, Florence, Italy
Department of Health Surveillance and Bioethics, Section of Legal Medicine, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168, Rome, 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, 11003, Cadiz, Spain
Brugada-Terradellas J:
Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), European Reference Network for Rare, 1105 AZ, Amsterdam, The Netherlands
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Cardiology Department, Sant Joan de Déu Hospital de Barcelona, 08950, Barcelona, Spain
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain
Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Arrítmies Pediàtriques, Cardiologia Genètica i Mort Sobtada, Esplugues de Llobregat, 08950, Barcelona, 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.
Green Submitted, hybrid
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