Tubular Aggregate Myopathy via the STIM1 Gene

Tubular aggregate myopathy (TAM, OMIM 160565) is a slowly progressive myopathy predominately affecting the proximal lower limbs. Presenting symptoms occur most commonly in childhood or adolescence and include falls and difficulty running (Böhm et al. 2013). Variable features among a cohort of published cases include proximal upper limb weakness, ophthalmoparesis, and contractures. Ptosis was not present in patients with ophthalmoparesis, and cardiac involvement was not observed in any of the reported cases. Serum CpK levels were elevated up to 27-times normal. EMG studies revealed a myopathic pattern. Type 2 fiber atrophy was observed in muscle biopsies, and ultrastructural analysis of muscle from affected individuals revealed massive tubular aggregates of sarcoplasmic origin (Böhm et al. 2013).

Age of onset among affected individuals from the four published families was most commonly childhood and adolescence with rare instances of adult onset or clinically asymptomatic individuals (Böhm et al. 2013).

Tubular aggregate myopathy is inherited as an autosomal dominant disorder. STIM1 encodes the 'stromal interaction molecule 1' protein, which is the primary calcium sensor in the endoplasmic reticulum. Pathogenic missense variants in the intraluminal calcium binding domain of STIM1 result in impaired calcium sensing (Böhm et al. 2013).

Analytical sensitivity should be high because all mutations reported are detectable by this method. Clinical sensitivity cannot be estimated because only a small number of patients have been reported.

This test provides full coverage of all coding exons of the STIM1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).