DYT1 Early-Onset Isolated Dystonia via the TOR1A Gene

DYT1 early-onset dystonia is one of the most common early-onset isolated dystonias, presenting in childhood or adolescence, typically before the age of 26 years. It is one of the most prevalent forms of inherited isolated dystonia. DYT1 dystonia usually starts in a leg (average age 9 years) or an arm (average age 15 years). Initially, dystonia is often detected in specific actions such as writing or walking. Gradually, foot, leg, or arm posturing caused by dystonic muscle contractions becomes the predominant feature (Ozelius and Bressman 2011). Dystonic muscle contractions may lead to gait disturbance, tremor or blepharospasm (Tuffery-Giraud et al. 2001). Depression has been reported in patients with DYT1 dystonia (Heiman et al. 2004). Dystonic movements are irreversible with relatively slow progression. However, clinical features and disease severity vary considerably even among members of the same family (Opal et al 2002).

DYT1 dystonia is estimated to affect 1-9 per million individuals worldwide. However, due to a founder variant, the disease is more prevalent in the Ashkenazi Jewish population, with a prevalence of 1 in 10,000 (Risch et al. 1995).

DYT1 early-onset dystonia is inherited in an autosomal dominant manner with incomplete penetrance. It is caused by a recurrent 3-bp deletion in the TOR1A gene, which results in the in-frame deletion of one of two conserved glutamic acid residues of the torsinA protein (c.904_906delGAG; p.Glu302del). This deletion has been reported in patients with DYT1 dystonia from various geographic and ethnic origins (Ozelius et al. 1997; Valente et al. 1999; Grundmann et al. 2003). It accounts for up to 53% of DYT1 early onset dystonia patients worldwide. Due to a founder effect, this deletion accounts for up to 90% of the disorder in the Ashkenazi Jewish population (Ozelius and Bressmann 2011). De novo occurrence of the deletion has been reported (Klein et al. 1998). Penetrance is reduced to 30%, with 70% of individuals who carry a disease-causing allele having no symptoms (Ozelius et al. 1997; Bressman et al. 2002). Heterozygous carriers for the p.Glu302del variant remain usually unaffected if symptoms do not appear before 26 years of age (Ozelius and Bressman 2011).

TOR1A encodes TorsinA, an ATP-binding protein. It is widely expressed in the substantia nigra of the midbrain, which plays an important role in reward and movement. The p.Glu302del variant is believed to induce premature degradation of the mutated protein (Ozelius et al. 1997; Giles et al. 2008).

This test will detect the c.904_906delGAG variant in up to 53% of patients with early-onset isolated dystonia in the non-Jewish populations and in up to 90% of patients of Ashkenazi Jewish ancestry (Ozelius and Bressman 2011).

No large copy number variations have been reported involving the TOR1A gene.

This test provides full coverage of all coding exons of the TOR1A 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).