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- Title
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.
- Authors
Gonzalez-Quereda, Lidia; Rodriguez, Maria Jose; 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 Jose; Jerico, Ivonne; Torne, Laura; Riera, Pau; Milisenda, Jose; Sanchez, Aurora; Garrabou, Gloria; Llano, Isabel
- Abstract
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.
- Subjects
SPAIN; NEUROMUSCULAR diseases; NEMALINE myopathy; NUCLEOTIDE sequencing; CONGENITAL myasthenic syndromes; MUSCULAR dystrophy; GENETIC disorders
- Publication
Genes, 2020, Vol 11, Issue 5, p539
- ISSN
2073-4425
- Publication type
Article
- DOI
10.3390/genes11050539