title: Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders.
abstract: BACKGROUND
  Neuromuscular disorders are a clinically, pathologically, and genetically heterogeneous group. Even for the experienced clinician, an accurate diagnosis is often challenging due to the complexity of these disorders. Here, we investigated the utility of next generation sequencing (NGS) in early diagnostic algorithms to improve the diagnosis for patients currently lacking precise molecular characterisation, particularly for hereditary myopathies.
  
  
  METHODS
  43 patients presenting with early onset neuromuscular disorders from unknown genetic origin were tested by NGS for 579 nuclear genes associated with myopathy.
  
  
  RESULTS
  In 21 of the 43 patients, we identified the definite genetic causes (48.8%). Additionally, likely pathogenic variants were identified in seven cases and variants of uncertain significance (VUS) were suspected in four cases. In total, 19 novel and 15 known pathogenic variants in 17 genes were identified in 32 patients. Collagen VI related myopathy was the most prevalent type in our cohort. The utility of NGS was highlighted in three cases with congenital myasthenia syndrome, as early diagnosis is important for effective treatment.
  
  
  CONCLUSIONS
  A targeted NGS can offer cost effective, safe and fairly rapid turnaround time, which can improve quality of care for patients with early onset myopathies and muscular dystrophies; in particular, collagen VI related myopathy and congenital myasthenia syndromes. Nevertheless, a substantial number of patients remained without molecular diagnosis in our cohort. This may be due to the intrinsic limitation of detection for some types of mutations by NGS or to the fact that other causative genes for neuromuscular disorders are yet to be identified.
authors: Division of Pediatric Neurology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
authors: Jong Hee
authors: JH
authors: Chae
authors: Seattle Children's Research Institute, Seattle, Washington, USA.
authors: Valeria
authors: V
authors: Vasta
authors: Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.
authors: Anna
authors: A
authors: Cho
authors: Division of Pediatric Neurology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
authors: Byung Chan
authors: BC
authors: Lim
authors: Seattle Children's Research Institute, Seattle, Washington, USA.
authors: Qing
authors: Q
authors: Zhang
authors: Department of Pediatrics, Korea University College of Medicine, Seoul, Korea.
authors: So Hee
authors: SH
authors: Eun
authors: Seattle Children's Research Institute, Seattle, Washington, USA Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Si Houn
authors: SH
authors: Hahn
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D024142:Collagen Type VI / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: C000601102:COL6A3 protein, human; D024142:Collagen Type VI; D016326:Extracellular Matrix Proteins
keywords: Molecular genetics; Motor neurone disease; Muscle disease; Neuromuscular disease; Peripheral nerve disease