LMNA-related muscular dystrophy: Identification of variants in alternative genes and personalized clinical translation
Por:
César-Díaz S, Coll, M, Fiol JV, Fernandez-Falgueras, A, Cruzalegui JC, Iglesias, A, Moll I, Perez-Serra, A, Martínez-Barrios E, Ferrer-Costa, C, del Olmo, B, Puigmulè, M, Alcalde, M, Lopez, L, Pico, F, Berrueco R, Brugada-Terradellas J, Zschaeck-Luzardo I, Natera-de Benito D, Carrera-García L, Exposito-Escudero JM, Ortez-Gonzalez CI, Nascimento-Osorio A, Brugada, R, Sarquella-Brugada G and Campuzano, O
Publicada:
24 mar 2023
Ahead of Print:
24 mar 2023
Resumen:
Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences.Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed.Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes.Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression.
Filiaciones:
César-Díaz S:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Coll, M:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Fiol JV:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Fernandez-Falgueras, A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Cruzalegui JC:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Iglesias, A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Moll I:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Perez-Serra, A:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Martínez-Barrios E:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Ferrer-Costa, C:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
del Olmo, B:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Puigmulè, M:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Medical Science Department, School of Medicine, Universitat de Girona, Girona, Catalonia, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Univ Girona, Sch Med, Med Sci Dept, Girona, Catalonia, Spain
Alcalde, M:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Lopez, L:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Pico, F:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Berrueco R:
Pediatric Hematology Service, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu de Barcelona (IRP-HSJD), Universitat de Barcelona, Barcelona, Spain
Univ Barcelona, Hosp St Joan de Deu Barcelona, Hosp St Joan de Deu Barcelona IRP HSJD, Inst Recerca Pediat,Pediat Hematol Serv, Barcelona, Spain
Brugada-Terradellas J:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Arrhythmia Section, Cardiology Service, Hospital Clínic, Barcelona, Spain
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Hosp Clin Barcelona, Cardiol Serv, Arrhythmia Sect, Barcelona, Spain
Zschaeck-Luzardo I:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Investigación Aplicada en Enfermedades Neuromusculares Neurociències Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Hosp St Joan de Deu, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Invest Aplicada Enfermedades Neuromusculares Neur, Esplugas de Llobregat, Spain
Natera-de Benito D:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Investigación Aplicada en Enfermedades Neuromusculares Neurociències Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
Hosp St Joan de Deu, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Invest Aplicada Enfermedades Neuromusculares Neur, Esplugas de Llobregat, Spain
Carrera-García L:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Investigación Aplicada en Enfermedades Neuromusculares Neurociències Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
Hosp St Joan de Deu, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Invest Aplicada Enfermedades Neuromusculares Neur, Esplugas de Llobregat, Spain
Exposito-Escudero JM:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Investigación Aplicada en Enfermedades Neuromusculares Neurociències Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
Hosp St Joan de Deu, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Invest Aplicada Enfermedades Neuromusculares Neur, Esplugas de Llobregat, Spain
Ortez-Gonzalez CI:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Investigación Aplicada en Enfermedades Neuromusculares Neurociències Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
Hosp St Joan de Deu, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Invest Aplicada Enfermedades Neuromusculares Neur, Esplugas de Llobregat, Spain
Nascimento-Osorio A:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Investigación Aplicada en Enfermedades Neuromusculares Neurociències Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
Instituto Nacional de Investigación Biomédica de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Hosp St Joan de Deu, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Invest Aplicada Enfermedades Neuromusculares Neur, Esplugas de Llobregat, Spain
Inst Salud Carlos III, Inst Nacl Invest Biomed Enfermedades Raras CIBERE, Madrid, Spain
Brugada, R:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Medical Science Department, School of Medicine, Universitat de Girona, Girona, Catalonia, Spain
Cardiology Department, Hospital Josep Trueta, Girona, Catalonia, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Univ Girona, Sch Med, Med Sci Dept, Girona, Catalonia, Spain
Hosp Josep Trueta, Cardiol Dept, Girona, Catalonia, Spain
Sarquella-Brugada G:
Pediatric Arrhythmias, Inherited Cardiac Diseases and Sudden Death Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Arrítmies Pediàtriques, Cardiologia Genètica i Mort sobtada, Malalties Cardiovasculars en el Desenvolupament, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, Netherlands
Medical Science Department, School of Medicine, Universitat de Girona, Girona, Catalonia, Spain
Hosp St Joan de Deu, Pediat Arrhythmias Inherited Cardiac Dis & Sudden, Barcelona, Spain
Inst Recerca St Joan de Deu, Arritmies Pediat Cardiol Genet & Mort Sobtada, Malalties Cardiovasc Desenvolupament, Barcelona, Spain
European Reference Network Rare Low Prevalence &, Amsterdam, Netherlands
Univ Girona, Sch Med, Med Sci Dept, Girona, Catalonia, Spain
Campuzano, O:
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Medical Science Department, School of Medicine, Universitat de Girona, Girona, Catalonia, Spain
Univ Girona, Cardiovasc Genet Ctr, IDIBGI, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Univ Girona, Sch Med, Med Sci Dept, Girona, Catalonia, Spain
Green Submitted, gold
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