WASHC5

Inheritance Pattern: AD

Disease ID:MONDO:0009073

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009073

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009073

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0019078

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009073

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011339

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0011339

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009073

Submitter: ClinGen

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 recessive Ritscher-Schinzel syndrome 1 in 2013 (Elliott et al., PMID: 24065355). This disorder is characterized by brain malformations, with neurodevelopmental findings, dysmorphic features, and cardiovascular malformations. *WASHC5* has also been associated with autosomal dominant hereditary spastic paraplegia 8 by Valdmanis et al. in 2007 (PMID: 17160902). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern and in clinical phenotype between the two disease assertions. Therefore, the diseases were split into Ritscher-Schinzel syndrome 1 (OMIM: 220210) and hereditary spastic paraplegia 8 (OMIM: 603563). The split curation for autosomal recessive hereditary spastic paraplegia 8 has been curated separately. Evidence supporting the relationship between *WASHC5* and Ritscher-Schinzel syndrome 1 includes case-level data. Elliott et al. (2013, PMID: 24065355) identified a homozygous canonical splice site variant in 10 affected individuals from an isolated First Nations community. A homozygous missense variant was identified in another individual but was not scored (Maddirevula et al., 2020, PMID: 33456446). This gene-disease relationship is not supported by experimental evidence. There are two animal models (one mouse and one zebrafish) reported in the literature but neither provide evidence to support the gene-disease relationship (Bu et al., PMID:32417190) In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on September 17, 2021. It was reevaluated on December 4, 2024 (SOP Version 11). Although a new case report was published (PMID: 36130690), the classification did not change.

Inheritance Pattern: AD

Disease ID:MONDO:0011339

Submitter: Orphanet