Submission Details

The WASHC5 gene is located on chromosome 8 at 8q24.13 and encodes the WASH complex subunit 5 protein, or strumpellin, a component of the WASH core complex, which activates Arp2/3-mediated actin polymerization and functions in endosome fission. WASHC5 was first reported in relation to autosomal dominant hereditary spastic paraplegia 8 in 2007 (Valdmanis et al., PMID: 17160902). This disorder is a slowly progressive, typically pure spastic paraplegia of the lower limbs characterized by pyramidal signs including hyperreflexia, extensor plantar reflexes, spasticity, and clonus without other neurological findings; mild distal decreased vibration sense; and urinary urgency that becomes apparent with spasticity. More complex phenotypic features may present, including ataxia, seizures, intellectual disability, dementia, muscle atrophy, extrapyramidal disturbance, and peripheral neuropathy. Onset is typically between 10 and 59 years of age and affected individuals often become wheelchair dependent. WASHC5 has also been associated with autosomal recessive Ritscher-Schinzel syndrome 1 by Elliott et al. in 2013 (PMID: 24065355). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is a difference in inheritance pattern and in clinical phenotype. Therefore, the diseases were split into hereditary spastic paraplegia 8 (OMIM: 603563) and Ritscher-Schinzel syndrome 1 (OMIM: 220210). The split curation for autosomal Ritscher-Schinzel syndrome 1 has been curated separately. Evidence supporting the relationship between WASHC5 and hereditary spastic paraplegia 8 includes case-level data and experimental data. Numerous unique variants have been reported in humans in multiple publications. While most reported variants are missense variants, putative loss-of-function variants are also identified in a small number of cases, including a small intragenic deletion (Ishiura et al., 2014, PMID: 24451228) Segregation of a variant with disease was demonstrated in several families (Valdmanis et al., 2007, PMID: 17160902). Additional variants were evaluated but not scored due to their presence at high frequency in public databases. The mechanism of disease has not yet been clearly established, but haploinsufficiency has been suggested (Clemen et al., 2010, PMID: 20833645). Small hairpin RNA-mediated strumpellin knockdown in human neuroblastoma cells showed a highly significant reduction of axonal outgrowth in the knockdown cells versus controls cells (Clemen et al. 2010; PMID: 20833645), while a knockdown zebrafish model recapitulated some aspects of the human phenotype (Valdmanis et al., 2007, PMID: 17160902). In summary, there is moderate evidence to support the association of WASHC5 with autosomal dominant hereditary spastic paraplegia 8. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 09.17.2021 (SOP Version 8). This GDR was reevaluated on 30 September, 2024 (SOP Version 10). Although three new case reports were published, the classification did not change.