Exome sequencing as a second-tier diagnostic approach for clinically suspected dysferlinopathy patients

Muscle Nerve. 2014 Dec;50(6):1007-10. doi: 10.1002/mus.24344. Epub 2014 Oct 30.


Introduction: 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.

Keywords: LGMD; diagnosis; distal myopathy; dysferlin exome.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Distal Myopathies / diagnosis
  • Distal Myopathies / genetics
  • Dysferlin
  • Exome / genetics*
  • Genetic Testing / methods*
  • Humans
  • Membrane Proteins / genetics
  • Muscle Proteins / genetics
  • Muscular Dystrophies, Limb-Girdle / diagnosis*
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Mutation / genetics
  • Sequence Analysis, DNA / methods*


  • DYSF protein, human
  • Dysferlin
  • Membrane Proteins
  • Muscle Proteins

Supplementary concepts

  • Dysferlinopathy