This study aimed to translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. WES was carried out on 60 families with LGMDs (100 exomes), who had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens. With WES, the authors achieved a diagnostic success rate of 45.0% in this difficult-to-diagnose cohort of patients with LGMD. This study expands the clinical phenotypes associated with known myopathy genes, and highlights the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum samples.
