Autosomal recessive muscular dystrophies are heterogeneous genetic disorders. To date, 39 genes are 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. In this study, the authors 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 of targeted DYSF analysis. Exome sequencing allowed 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. Exome sequencing associated with data filtering constitutes an efficient second-tier analysis for genes implicated in LGMD or distal myopathies.
