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

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. Muscle Nerve 50: 1007–1010, 2014