title: Exome sequencing as a second-tier diagnostic approach for clinically suspected dysferlinopathy patients.
abstract: BACKGROUND
  Autosomal recessive muscular dystrophies are heterogeneous genetic disorders, with 39 genes currently implicated. Genetic diagnosis using targeted single-gene analysis by Sanger sequencing yields negative results in 10-20% of samples, warranting clinical re-evaluation and time-consuming testing of additional genes. This applies to dysferlinopathies caused by mutations in the gene encoding dysferlin (DYSF), which presents mainly as limb-girdle muscular dystrophy (LGMD) or distal myopathy.
  
  
  METHODS
  We evaluated exome sequencing associated with data filtering for selected genes as a second-tier approach for genetic diagnosis in a cohort of 37 patients with an initial negative result on targeted DYSF analysis.
  
  
  RESULTS
  Exome sequencing allowed for establishing (16%) or suggesting (8%) the molecular diagnosis by implicating other known LGMD or distal myopathy genes or by revealing DYSF mutations previously missed using mutation-screening techniques with incomplete detection yields.
  
  
  CONCLUSIONS
  Exome sequencing associated with data filtering constitutes an efficient second-tier analysis for genes implicated in LGMD or distal myopathies.
authors.affiliation: Aix Marseille Université, INSERM, GMGF, UMR_S 910, 13385, Marseille, France; APHM, Département de Génétique Médicale, Hôpital Timone Enfants, Marseille, 13385, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Desvignes
authors.forename: Levy
authors.initials: L
authors.lastname: Nicolas
authors.forename: Krahn
authors.initials: K
authors.lastname: Martin
mesh_terms: D015331:Cohort Studies; D049310:Distal Myopathies / Q000175:diagnosis / Q000235:genetics; D000073939:Dysferlin; D059472:Exome / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins
keywords: LGMD; diagnosis; distal myopathy; dysferlin exome