Dystonia via the ANO3 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 ANO3 gene have been implicated in isolated dystonia in several geographical and ethnical populations (Charlesworth et al. 2012; Stamelou et al. 2014; Ma et al. 2015). In these patients, dystonia usually has onset during the fourth decade of life. However, childhood onset has been described. In most cases, dystonia begins in the neck. Tremor is a prominent feature in patients with ANO3-related dystonia, resulting often in a misdiagnosis for essential tremor. Tremor affects several parts of the body, including the head, neck, trunk and limbs. The voice and posture are also affected. Tremor appears to be aggravated by stress. Additional features include myoclonic jerks, laryngeal dysphonia, torticollis, blepharospasm, and shaky writing. Dystonic movements gradually expand to other parts of the body and progress to generalized dystonia in about 10% of cases (Ma et al. 2015). ANO3 pathogenic variants have been reported mostly in familial cases. A de novo pathogenic variant has been documented in one patient with the sporadic form of the disorder (Zech et al. 2017). Reduced penetrance is speculated based on the history of the disease in several families (Charlesworth et al. 2012, Stamelou et al. 2014).

Four causative variants in the ANO3 gene have been reported to date for dystonia. All four variants are missense. Evidence for pathogenicity included co-segregation of the variants in several families with the history of isolated dystonia with craniofacial involvement and tremor (Human Gene Mutation Database).

ANO3 encodes anoctamin3 protein, a calcium-dependent channel transmembrane protein (Charlesworth 2012).

ANO3 pathogenic variants have been identified in about 1% of patients with predominantly craniocervical dystonia (Zech et al. 2017).

This test provides full coverage of all coding exons of the ANO3 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).