Spastic Paraplegia 12 via the RTN2 Gene

Spastic Paraplegia 12 (SPG12) is a type of hereditary spastic paraplegia (HSP), characterized by spasticity and hyperreflexia in lower limbs. Some patients may also have urinary symptoms and distal sensory impairments. SPG12 has been described in a Welsh family and an Italian family. The age at onset of SPG12 is variable and averages about 10 years (Reid et al. 2000; Orlacchio et al. 2002). Typically, SPG12 is a pure form of HSP with rapid progression, and most patients become wheelchair-bound within a couple of years after onset (Reid et al. 2000).

The transmission pattern of SPG12 in reported cases is consistent with autosomal dominant inheritance (Reid et al. 2000; Orlacchio et al. 2002). Montenegro et al. (2012) mapped SPG12 to RTN2. RTN2 belongs to the reticulon encoding gene family. RTN2 contains a uniquely conserved C-terminal domain (RHD, reticulon homology domain) and regulates ER structure and functions (Chiurchiu et al. 2014). RTN2 interacts with other proteins implicated in HSP, e.g., spastin (SPG4), atlastin-1 (SPG3A) and REEP1 (SPG31). These proteins form a complex to shape ER into sheets and tubules. To date, only 3 pathogenic variants have been identified in the RTN2 gene (Human Gene Mutation Database). Montenegro et al. (2012) found a heterozygous 1-bp duplication (c.178dupC) and a heterozygous complete deletion of the RTN2 gene. Neveling et al. (2013) identified a 1-bp deletion (c.939delT).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. Pathogenic variants in RTN2 appear to be a rare cause of spastic paraplegia.

This test provides full coverage of all coding exons of the RTN2 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).