Hereditary Spastic Paraplegia via the ATP2B4 (PMCA4) Gene

Hereditary Spastic Paraplegia (HSP) is a group of clinically and genetically diverse diseases, characterized by spasticity (rigid muscles) and lower extremity weakness (Fink 2014; Hensiek et al. 2015). To date, more than 70 forms of HSP have been described (Tesson et al. 2015). In a two-generation Chinese family with 6 members (4 were symptomatic and 2 were asymptomatic), Li et al. reported a form of autosomal dominant HSP (Li et al. 2014). Affected individuals in this family developed progressive spastic paraplegia since teenage or mid-30s. They manifested weakness in hip and knee flexion, and downgoing plantar responses. The disease seems to be a “pure” type, as the patients’ upper limbs remained unaffected and no cognitive dysfunction was involved (Li et al. 2014).

Based on the Chinese family studied, the disease is inherited in an autosomal dominant manner. By whole exome sequencing, Li et al. identified a missense variant (c.803G>A, p.Arg268Gln) in the Plasma Membrane Calcium ATPase gene (PMCA4, also known as ATP2B4) (Li et al. 2014). This is the only pathogenic variant identified so far in the ATP2B4 gene (Human Gene Mutation Database). ATP2B4 is involved in calcium homeostasis (Kunert-Keil et al. 2014), and the p.Arg268Gln pathogenic variant in ATP2B4 may cause delay in intracellular calcium extrusion (Ho et al. 2015).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. The only reported pathogenic variant, c.803G>A, is detectable by sequencing.

This test provides full coverage of all coding exons of the ATP2B4 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).