In this study, the authors performed whole-exome sequencing and targeted exome sequencing in order to identify the genetic etiology and characterise the clinicopathologic features of a novel distal myopathy. They also evaluated the pathogenicity of identified mutations using immunohistochemistry, Western blot analysis, and expression studies. Sequencing identified a likely pathogenic c.1165+1 G>A splice donor variant in SQSTM1 in the affected members of 1 family and in an unrelated patient with sporadic distal myopathy. Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions. SQSTM1 is an autophagic adaptor that shuttles aggregated and ubiquitinated proteins to the autophagosome for degradation via its C-terminal UBA domain. Similar to mutations in VCP, dominantly inherited mutations in SQSTM1 are now associated with rimmed vacuolar myopathy, Paget disease of bone, amyotrophic lateral sclerosis, and frontotemporal dementia. The results of this study further suggest a pathogenic connection between the disparate phenotypes.
