Dystonia via the THAP1 Gene

Dystonia has been recently re-defined by an international panel as: “a movement disorder characterized by sustained and intermittent muscle contractions, causing abnormal, often repetitive, movements, postures or both. Dystonic movements are typically patterned, twisting and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.” (Albanese et al. 2013).

Dystonia is a clinically heterogeneous disorder in regards to age of onset, distribution, and the occurrence of another movement disorder, including parkinsonism, myoclonus, and dyskinesia. Additional neurological manifestations reported in patients with the complex form of the disease include ataxia, oculomotor dysfunction and cognitive impairment. Age of onset varies from early infancy to late adulthood. Four types are distinguished based on the part of the body that is affected: (1) focal, if only one part of the body is affected; (2) segmental, if contiguous regions are affected; (3) multifocal, if non-contiguous regions are affected; and (4) generalized, if at least three parts of the body are affected, including the trunk and one leg (Klein et al. 2014; Lohmann and Klein 2017; Williams et al. 2017).

Based on the absence or presence of additional symptoms, three subtypes of dystonia are recognized. These include: (1) Isolated dystonia, when dystonic movements, with or without tremor, occur in isolation. (2) Combined dystonia, when dystonic movements are accompanied by additional movement disorders. (3) Complex dystonia, when dystonia occurs in the presence of additional neurological and/or systemic symptoms (Albanese et al. 2013; Klein et al. 2014; Camargo et al. 2015).

Isolated dystonia is estimated to affect about 16 in 100,000 individuals (Steeves et al. 2012).

To date, four genes have been conclusively implicated in isolated dystonia: TOR1A, THAP1, GNAL and ANO3. Pathogenic variants in all four genes are inherited in an autosomal dominant manner.

Pathogenic variants in the THAP1 gene have been implicated in isolated dystonia in several geographical and ethnical populations (Fuchs et al. 2009; da Silva-Junior et al. 2014; Dobrivic et al. 2013; Miyamoto et al. 2014). In these patients, dystonia is characterized by an onset during the second decade of life. However, childhood and late adulthood onset have been described (Bressman et al. 2009). In about half the cases, dystonia begins in the face, jaw, tongue (cranial dystonia) or neck (cervical dystonia). In the other half, dystonic movements appear in the arms or legs. Additional clinical features include voice changes in the form of dysphonia and speech abnormalities due to the laryngeal and pharyngeal dystonia; tremor and writer’s cramp (Fuchs et al. 2009; Miyamoto et al. 2014). Dystonic movements gradually expand to other parts of the body and progress to generalized dystonia in a significant fraction of cases (da Silva-Junior et al. 2014). Although most reported cases are inherited from an affected parent, isolated cases have been described (Paisán-Ruiz et al. 2009). THAP1 pathogenic variants are inherited with reduced penetrance, ranging between 60% and 72%. Men and women are affected equally (da Silva-Junior et al. 2014; Fuchs et al. 2009).

About 90 causative variants in the THAP1 gene have been reported to date. Two thirds are missense. With one exception, the remaining are truncating and include nonsense, splicing and small insertions (Human Gene Mutation Database). The exception consists of a small deletion that is predicted to result in the in-frame deletion of a single amino acid residue (Groen et al. 2010).

THAP1 codes for THAP domain-containing protein 1, a transcription factor that has been shown to physically interact with TOR1A promoter, indicating a functional link between two dystonia genes (Gavarini et al. 2010).

THAP1 pathogenic variants have been identified in about 2.5% of patients with isolated dystonia (LeDoux et al. 2016).

This test provides full coverage of all coding exons of the THAP1 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).