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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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