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

Genes (Basel). 2020 May 11;11(5):539. doi: 10.3390/genes11050539.


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.

Keywords: congenital myasthenic syndromes; congenital myopathies; muscular dystrophies; neuromuscular diseases; targeted next-generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • DNA Mutational Analysis / methods*
  • Female
  • Genetic Association Studies / methods
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / epidemiology
  • Mitochondrial Diseases / genetics
  • Muscular Diseases / diagnosis
  • Muscular Diseases / epidemiology
  • Muscular Diseases / genetics
  • Mutation*
  • Neuromuscular Diseases / diagnosis
  • Neuromuscular Diseases / epidemiology
  • Neuromuscular Diseases / genetics*
  • Spain / epidemiology
  • Young Adult