Welander Distal Myopathy via the TIA1 Gene

Welander distal myopathy (OMIM 604454) is an adult onset disorder characterized by weakness and wasting of hand muscles with slow progression to involve the leg muscles. The presenting clinical sign is usually fine motor clumsiness involving the index finger and thumb (Ahlberg et al. 1999). Atrophy of the hand muscles occurs over time. Gait difficulties including stumbling and falls develop because of anterior tibial muscle weakness and subsequent inability to raise the foot normally. Muscle biopsies from patients show variable fiber diameter, atrophic fibers, and rimmed vacuoles (Klar et al. 2013). Immunostaining of atrophic muscle reveals TIA1-positive cytoplasmic aggregates or granules (Hackman et al. 2013).

Welander distal myopathy is typically an autosomal dominant disorder limited to individuals of Nordic heritage (Hackman et al. 2013). All Welander distal myopathy patients reported to date have the same missense variant (p.Glu384Lys) in the TIA1 gene (OMIM 603518). Because the p.Glu384Lys variant is relatively common in Finland and Sweden, at least one homozygous patient has been reported (Ahlberg et al. 1999). The patient was affected earlier in life and proximal muscle involvement was present. TIA1 encodes a stress-induced, RNA-binding protein which participates in regulation of gene expression through splicing regulation and translational repression.

The TIA1cytotoxic granule-associated RNA-binding protein' is coded by exons 1-13 of the TIA1 gene located on chromosome 2p13.3.

To date, the only known cause of Welader distal myopathy is the p.Glu384Lys mutation in exon 13 of the TIA1 gene. Clinical and analytical sensitivity should be high for symptomatic individuals of Nordic heritage.

This test provides full coverage of all coding exons of the TIA1 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).