Spinocerebellar Ataxia 21 via the TMEM240 Gene

The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of inherited neurological disorders characterized by degeneration of neurons in the cerebellum and associated pathways. The SCAs are classified according to the genetic loci: SCA1 through SCA40 (Tsoi et al. 2014). Slowly progressive cerebellar dysfunction is a feature of each type of SCA syndrome in association with various oculomotor, pyramidal/extrapyramidal, sensory, and cognitive/behavioral symptoms that vary with the underlying affected gene. There is great variability in the age of onset, associated symptoms and disease progression (Bushart et al. 2016; Meera et al. 2016).

Spinocerebellar Ataxia 21 (SCA21) was reported in a four generation French family with characteristics including early onset, mild to severe cognitive impairment, motor clumsiness, and slow progression (Vuillaume et al. 2002). Analysis of 368 additional French families with autosomal dominant cerebellar ataxia identified 6 different heterozygous pathogenic variants in the TMEM240 gene (Delplanque et al. 2014).

Spinocerebellar ataxia 21 (SCA21) is an autosomal dominant neurologic disorder caused by pathogenic variants in TMEM240 (Delplanque et al. 2014). TMEM240 encodes a transmembrane-domain containing protein expressed in the brain and cerebellum. TMEM240 contains four exons, encodes 173 amino acids and is located at 1p36.33. The mechanism by which pathogenic variants in TMEM240 cause SCA21 disease remains unclear. It is possible that variants in the membrane-spanning protein TMEM240 interfere with the function of other channel proteins in the neuronal cell membrane (Zeng et al. 2016). Most reported pathogenic variants in TMEM240 are missense or nonsense. No large deletions or duplications have been reported.

Precise estimates of clinical sensitivity are not available because only a limited number of patients have been reported. However, pathogenic TMEM240 variants are not a common cause of Spinocerebellar Ataxia.

This test provides full coverage of all coding exons of the TMEM240 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).