Spastic Paraplegia 8 via the WASHC5/KIAA0196 Gene

Spastic paraplegia 8 (SPG8) is a type of hereditary spastic paraplegia (HSP) and is characterized by slowly progressive spasticity and weakness of lower limbs (Valdmanis et al. 2008). It is a “pure” form of HSP, i.e., the symptoms are limited to lower limbs. Some affected individuals may demonstrate decreased vibration sense and urinary urgency (Depienne et al. 2007). Interfamilial and intrafamilial phenotypic variation is common. On average, the age of onset is in 20s and 30s (Valdmanis et al. 2008). Generally, SPG8 is a severe type of HSP compared to many other types, and most patients with SPG8 become wheelchair bound by age 40 years (Hedera et al. 1999; Reid et al. 1999).

SPG8 is indistinguishable clinically from many others forms of HSP, such as SPG3A, SPG4, SPG6, SPG10, SPG12, SPG13 and SPG19. Therefore, molecular genetic testing is very useful in a precise diagnosis of this disease.

SPG8 is inherited in an autosomal dominant (AD) manner, and the penetrance is approximately 90%-100% (Valdmanis et al. 2008). SPG8 is caused by pathogenic variants in the WASHC5/KIAA0196 gene (Valdmanis et al. 2007), which is the only known causative gene for SPG8. WASHC5 encodes the protein strumpellin, a 1159-residue protein containing one spectrin repeat and a domain of unknown significance with high level of conservation (Valdmanis et al. 2007). To date, ten missense variants and one gross deletion have been identified in WASHC5 to cause SPG8 (Human Gene Mutation Database; Ichinose et al. 2016). Of note, it seems that all the known pathogenic variants for SPG8 cluster in the central part of the strumpellin protein. The strumpellin protein also physically binds VCP (valosin-containing protein), which is also involved in spastic paraplegia (de Bot et al. 2012)

Elliott et al. identified a homozygous splice site variant in the WASHC5 gene, which is causative for a developmental malformation syndrome, Ritscher-Schinzel Syndrome 1 (RTSC1) (Elliott et al. 2013).

WASHC5 pathogenic variants have been reported in a few SPG8 families; however, it is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies.

This test provides full coverage of all coding exons of the WASHC5 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).