Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
Por:
Gonzalez-Quereda L, Rodriguez MJ, Diaz-Manera J, Alonso-Perez J, Gallardo E, Nascimento-Osorio A, Ortez-Gonzalez CI, Benito DN, Olive-Valls M, Gonzalez-Mera L, Munain AL, Zulaica M, Poza JJ, Jerico I, Torne L, Riera P, Milisenda J, Sanchez A, Garrabou G, Llano I, Madruga-Garrido M and Gallano P
Publicada:
1 may 2020
Ahead of Print:
11 may 2020
Resumen:
The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such asTTN,NEBandRYR1.We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes,TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients' clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.
Filiaciones:
Gonzalez-Quereda L:
Genetics Department Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Rodriguez MJ:
Genetics Department Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
Diaz-Manera J:
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Neuromuscular Unit, Neurology Department, Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
Alonso-Perez J:
Neuromuscular Unit, Neurology Department, Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
Gallardo E:
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Neuromuscular Unit, Neurology Department, Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
Nascimento-Osorio A:
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain
Ortez-Gonzalez CI:
Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain
Benito DN:
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain
Olive-Valls M:
Neuropathology Unit, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, 08907 Barcelona, Spain
Gonzalez-Mera L:
Neuropathology Unit, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, 08907 Barcelona, Spain
Department of Neurology, Hospital de Viladecans, 08840 Barcelona, Spain
Munain AL:
Biodonostia, Neurosciences Area, Neuromuscular Diseases Laboratory, San Sebastian, 20014 Basque Country, Spain
CIBERNED, Instituto de Salud Carlos III, Ministry of Science, Innovation and Universities, 28029 Madrid, Spain
Department of Neurology, Hospital Universitario Donostia, San Sebastian, 20014 Basque Country, Spain
Department of Neurosciences, Faculty of Medicine and Dentistry, UPV-EHU, San Sebastian, 48940 Basque Country, Spain
Zulaica M:
Biodonostia, Neurosciences Area, Neuromuscular Diseases Laboratory, San Sebastian, 20014 Basque Country, Spain
CIBERNED, Instituto de Salud Carlos III, Ministry of Science, Innovation and Universities, 28029 Madrid, Spain
Poza JJ:
Department of Neurology, Hospital Universitario Donostia, San Sebastian, 20014 Basque Country, Spain
Jerico I:
Navarre Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
Department of Neurology, Complejo Hospitalario de Navarra, 31008 Pamplona, Spain
Torne L:
Navarre Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
Riera P:
Genetics Department Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
Milisenda J:
Hospital Clinic de Barcelona and Universidad de Barcelona, 08036 Barcelona, Spain
Sanchez A:
Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, 08036 Barcelona, Spain
Garrabou G:
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Cellex, IDIBAPS, University of Barcelona-Hospital Clínic of Barcelona, 08036 Barcelona, Spain
Llano I:
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Biocruces Bizkaia Health Research Institute, Barakaldo, 48903 Bizkaia, Spain
Genetics Service, Cruces University Hospital, Osakidetza Basque Health Service, Barakaldo, 48903 Bizkaia, Spain
Madruga-Garrido M:
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, 41013 Sevilla, Spain
Neuromuscular Disorder Unit, Pediatric Neurology Department, Hospital U. Virgen del Rocío, 41013 Sevilla, Spain
Gallano P:
Genetics Department Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Green Submitted, Green Published, gold
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