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Open AccessFeature PaperArticle

Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain

1
Genetics Dept. Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
2
U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
3
Neuromuscular Unit, Neurology Dept., Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
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Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain
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Neuropathology Unit, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, 08907 Barcelona, Spain
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Department of Neurology, Hospital de Viladecans, 08840 Barcelona, Spain
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Biodonostia, Neurosciences Area, Neuromuscular diseases Laboratory, San Sebastian, 20014 Basque Country, Spain
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CIBERNED, Instituto de Salud Carlos III, Ministry of Science, Innovation and Universities, 28029 Madrid, Spain
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Department of Neurology, Hospital Universitario Donostia, San Sebastian, 20014 Basque Country, Spain
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Department of Neurosciences, Faculty of Medicine and Dentistry, UPV-EHU, San Sebastian, 48940 Basque Country, Spain
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Navarre Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
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Department of Neurology, Complejo Hospitalario de Navarra, 31008 Pamplona, Spain
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Hospital Clinic de Barcelona and Universidad de Barcelona, 08036 Barcelona, Spain
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Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, 08036 Barcelona, Spain
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Cellex, IDIBAPS, University of Barcelona-Hospital Clínic of Barcelona, 08036 Barcelona, Spain
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Biocruces Bizkaia Health Research Institute, Barakaldo, 48903 Bizkaia, Spain
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Genetics Service, Cruces University Hospital, Osakidetza Basque Health Service, Barakaldo, 48903 Bizkaia, Spain
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Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, 41013 Sevilla, Spain
19
Neuromuscular Disorder Unit, Pediatric Neurology Department, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain
*
Author to whom correspondence should be addressed.
Genes 2020, 11(5), 539; https://doi.org/10.3390/genes11050539
Received: 24 April 2020 / Revised: 6 May 2020 / Accepted: 8 May 2020 / Published: 11 May 2020
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 as TTN, NEB and RYR1. 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. View Full-Text
Keywords: neuromuscular diseases; congenital myopathies; muscular dystrophies; congenital myasthenic syndromes; targeted next-generation sequencing neuromuscular diseases; congenital myopathies; muscular dystrophies; congenital myasthenic syndromes; targeted next-generation sequencing
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Figure 1

MDPI and ACS Style

Gonzalez-Quereda, L.; Rodriguez, M.J.; Diaz-Manera, J.; Alonso-Perez, J.; Gallardo, E.; Nascimento, A.; Ortez, C.; Natera-de Benito, D.; Olive, M.; Gonzalez-Mera, L.; Lopez de Munain, A.; Zulaica, M.; Poza, J.J.; Jerico, I.; Torne, L.; Riera, P.; Milisenda, J.; Sanchez, A.; Garrabou, G.; Llano, I.; Madruga-Garrido, M.; Gallano, P. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes 2020, 11, 539. https://doi.org/10.3390/genes11050539

AMA Style

Gonzalez-Quereda L, Rodriguez MJ, Diaz-Manera J, Alonso-Perez J, Gallardo E, Nascimento A, Ortez C, Natera-de Benito D, Olive M, Gonzalez-Mera L, Lopez de Munain A, Zulaica M, Poza JJ, Jerico I, Torne L, Riera P, Milisenda J, Sanchez A, Garrabou G, Llano I, Madruga-Garrido M, Gallano P. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes. 2020; 11(5):539. https://doi.org/10.3390/genes11050539

Chicago/Turabian Style

Gonzalez-Quereda, Lidia; Rodriguez, Maria J.; Diaz-Manera, Jordi; Alonso-Perez, Jorge; Gallardo, Eduard; Nascimento, Andres; Ortez, Carlos; Natera-de Benito, Daniel; Olive, Montse; Gonzalez-Mera, Laura; Lopez de Munain, Adolfo; Zulaica, Miren; Poza, Juan J.; Jerico, Ivonne; Torne, Laura; Riera, Pau; Milisenda, Jose; Sanchez, Aurora; Garrabou, Gloria; Llano, Isabel; Madruga-Garrido, Marcos; Gallano, Pia. 2020. "Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain" Genes 11, no. 5: 539. https://doi.org/10.3390/genes11050539

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