HIKESHI was first reported in relation to autosomal recessive hypomyelinating leukodystrophy-13 (OMIM: 616881) in 2016 (Edvardson et al., PMID: 26545878). Hikeshi protein function is essential to cell viability in conditions of heat stress and mediates the heat stress-induced nuclear import of heat shock protein (Hsp70) through a nuclear pore complex (Helman et al 2021, PMID: 34111619). This disease is clinically characterized by early onset global developmental delay, hypotonia evolving to dystonia or spastic quadriplegia, intellectual disability, and additional variable findings including neurodevelopmental regression, failure to thrive, ocular/visual abnormalities, and microcephaly (PMID: 34111619). Neuroimaging shows diffuse hypomyelination and thin corpus callosum (PMID: 34111619).
Three unique missense variants that have been reported in the homozygous state in twelve probands across five publications are included in this curation (PMIDs: 26545878, 28000699, 31912665, 34111619, 38922739). All three missense variants have supporting functional data. Of note, one variant (c.160C>G (p.Val54Leu)) was observed in 10 probands of Ashkenazi Jewish descent and is likely a founder variant in this population. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function.
This gene-disease relationship is also supported by an animal model. HIKESHI conditional knockout mice displayed a reduced number of myelinated axons when compared to wildtype mice, as well as decreased thickness of the myelin (PMID: 37865085). These characteristics resemble the human phenotype of hypomyelination.
In summary, there is definitive evidence supporting the relationship between HIKESHI and autosomal recessive hypomyelinating leukodystrophy-13 (MONDO:0014813), also known as HIKESHI-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date October 9, 2024 (SOP Version 11).
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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