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

Genes

Miren Zulaica¹  AdolfoLopez de Munain¹  Aurora Sanchez²  JuanJose Poza³  Pia Gallano⁴  MariaJose Rodriguez⁴  Lidia Gonzalez-Quereda⁴  Pau Riera⁴  Jose Milisenda⁵  Marcos Madruga-Garrido⁶  Laura Torne⁷  Ivonne Jerico⁷  Jorge Alonso-Perez⁸  Carlos Ortez⁹  Laura Gonzalez-Mera^1,10  Montse Olive^1,10  Isabel Llano^1,11  Eduard Gallardo^1,11  Jordi Diaz-Manera^1,11  Gloria Garrabou^1,11  DanielNatera-de Benito^1,11  Andres Nascimento^1,11 

[1] Biodonostia, Neurosciences Area, Neuromuscular Diseases Laboratory, San Sebastian, 20014 Basque Country, Spain;Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, 08036 Barcelona, Spain;Department of Neurology, Hospital Universitario Donostia, San Sebastian, 20014 Basque Country, Spain;Genetics Department Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain;Hospital Clinic de Barcelona and Universidad de Barcelona, 08036 Barcelona, Spain;Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, 41013 Sevilla, Spain;Navarre Institute for Health Research (IdiSNA), 31008 Pamplona, Spain;Neuromuscular Unit, Neurology Department, Hospital de Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain;Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain;Neuropathology Unit, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, 08907 Barcelona, Spain;U705, U762, U703, 722 and GCV4 for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain;

关键词: neuromuscular diseases;    congenital myopathies;    muscular dystrophies;    congenital myasthenic syndromes;    targeted next-generation sequencing;   

DOI  :  10.3390/genes11050539

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown