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

: 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. Muscle Nerve 50: 1007–1010, 2014