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, A, Ortez, C, Natera-de Benito, D, Olive, M, Gonzalez-Mera, L, de Munain, AL, Zulaica, M, Poza, JJ, Jerico, I, Tome, L, Riera, P, Milisenda, J, Sanchez, A, Garrabou, G, Llano, I, Madruga-Garrido, M, Gallano, P
Publicada:
1 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:
Hosp Santa Creu & Sant Pau, IIB St Pau, Genet Dept, Barcelona 08041, Spain
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Rodriguez, MJ:
Hosp Santa Creu & Sant Pau, IIB St Pau, Genet Dept, Barcelona 08041, Spain
Diaz-Manera, J:
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Hosp Santa Creu & Sant Pau, Neurol Dept, Neuromuscular Unit, IIB St Pau, Barcelona 08041, Spain
Alonso-Perez, J:
Hosp Santa Creu & Sant Pau, Neurol Dept, Neuromuscular Unit, IIB St Pau, Barcelona 08041, Spain
Gallardo, E:
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Hosp Santa Creu & Sant Pau, Neurol Dept, Neuromuscular Unit, IIB St Pau, Barcelona 08041, Spain
Nascimento, A:
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Hosp St Joan de Deu, St Res Inst Joan de Deu, Neuropaediat Dept, Neuromuscular Unit, Barcelona 08950, Spain
Ortez, C:
Hosp St Joan de Deu, St Res Inst Joan de Deu, Neuropaediat Dept, Neuromuscular Unit, Barcelona 08950, Spain
Natera-de Benito, D:
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Hosp St Joan de Deu, St Res Inst Joan de Deu, Neuropaediat Dept, Neuromuscular Unit, Barcelona 08950, Spain
Olive, M:
IDIBELL Hosp Bellvitge, Dept Pathol, Neuropathol Unit, Barcelona 08907, Spain
IDIBELL Hosp Bellvitge, Neuromuscular Unit, Dept Neurol, Barcelona 08907, Spain
Gonzalez-Mera, L:
IDIBELL Hosp Bellvitge, Dept Pathol, Neuropathol Unit, Barcelona 08907, Spain
IDIBELL Hosp Bellvitge, Neuromuscular Unit, Dept Neurol, Barcelona 08907, Spain
Hosp Viladecans, Dept Neurol, Barcelona 08840, Spain
de Munain, AL:
Neuromuscular Dis Lab, Biodonostia, Neurosci Area, San Sebastian 20014, Basque Country, Spain
Inst Salud Carlos III, Minist Sci Innovat & Univ, CIBERNED, Madrid 28029, Spain
Hosp Univ Donostia, Dept Neurol, San Sebastian 20014, Basque Country, Spain
Univ Basque Country, Dept Neurosci, Fac Med & Dent, San Sebastian 48940, Basque Country, Spain
Zulaica, M:
Neuromuscular Dis Lab, Biodonostia, Neurosci Area, San Sebastian 20014, Basque Country, Spain
Inst Salud Carlos III, Minist Sci Innovat & Univ, CIBERNED, Madrid 28029, Spain
Poza, JJ:
Hosp Univ Donostia, Dept Neurol, San Sebastian 20014, Basque Country, Spain
Jerico, I:
Navarre Inst Hlth Res IdiSNA, Pamplona 31008, Spain
Complejo Hosp Navarra, Dept Neurol, Pamplona 31008, Spain
Tome, L:
Navarre Inst Hlth Res IdiSNA, Pamplona 31008, Spain
Riera, P:
Hosp Santa Creu & Sant Pau, IIB St Pau, Genet Dept, Barcelona 08041, Spain
Milisenda, J:
Hosp Clin Barcelona, Barcelona 08036, Spain
Univ Barcelona, Barcelona 08036, Spain
Sanchez, A:
Hosp Clin Barcelona, Dept Biochem & Mol Genet, Barcelona 08036, Spain
Garrabou, G:
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Univ Barcelona, IDIBAPS, Cellex, Hosp Clin Barcelona, Barcelona 08036, Spain
Llano, I:
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Biocruces Bizkaia Hlth Res Inst, Baracaldo 48903, Bizkaia, Spain
Cruces Univ Hosp, Genet Serv, Osakidetza Basque Hlth Serv, Baracaldo 48903, Bizkaia, Spain
Madruga-Garrido, M:
Univ Seville, Hosp Univ Virgen del Rocio, CSIC, Inst Biomed Sevilla IBiS, Seville 41013, Spain
Hosp Univ Virgen del Rocio, Pediat Neurol Dept, Neuromuscular Disorder Unit, Seville 41013, Spain
Gallano, P:
Hosp Santa Creu & Sant Pau, IIB St Pau, Genet Dept, Barcelona 08041, Spain
Inst Salud Carlos III, U705, U762, U703, Madrid 28029, Spain
Inst Salud Carlos III, GCV4 Biomed Res Rare Dis CIBERER, Madrid 28029, Spain
Gold, Green Published
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