Spastic Paraplegia 48 via the AP5Z1 Gene

Spastic paraplegia 48 (SPG48) is a type of hereditary spastic paraplegia (HSP) characterized by spasticity and weakness of the lower limbs resulting in walking abnormalities. Additional features may include ataxia, sensory and motor neuropathy, urinary incontinence, mild cognitive impairment and parkinsonism (Hirst et al. 2015). SPG48 has been reported in a small number of patients. Most patients have disease onset in their 50s or 60s, although early onset has been reported in one patient (Slabicki et al. 2010; Pensato et al. 2014; Hirst et al. 2015).

The transmission pattern of SPG48 in the reported families is consistent with autosomal recessive (AR) inheritance. This disorder is caused by pathogenic variants in AP5Z1 gene (previously known as KIAA0415) (Slabicki et al. 2010). To date, different types of pathogenic variants (missense, nonsense and small deletions resulting in frameshifts) have been found in this gene to cause SPG48 (Human Gene Mutation Database). AP5Z1 encodes a subunit of the adaptor protein 5 complex (AP5), AP5 –Zeta, with both cytoplasmic and nuclear localization, involved in DNA damage repair (Slabicki et al. 2010). AP5Z1 might be also involved in intracellular sorting and trafficking of cargo proteins (Hirst et al. 2011).

It is difficult to estimate the exact clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants in the AP5Z1 gene reported to date can be detected by sequencing.

This test provides full coverage of all coding exons of the AP5Z1 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).