EIF2B3 was first associated with autosomal recessive leukoencephalopathy with vanishing white matter in 2002 (van der Knapp., PMID: 11835386). Individuals with EIF2B3-related leukoencephalopathy present with gait dysfunction, spasticity, cognitive decline, and white matter abnormalities on MRI. Some individuals develop ovarian failure. Onset is variable from infancy to adulthood, and progression of disease is often in the setting of fever, trauma, or stress. Vanishing white matter disease has also been referred to as Childhood Ataxia with Central Nervous System Hypomyelination (CACH). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that a phenotypic spectrum exists and there is no difference in molecular mechanism or inheritance pattern. Therefore, we chose to curate this gene-disease relationship under the disease term leukoencephalopathy with vanishing white matter 3 (OMIM:606273, MONDO:0957871).
Sixteen variants (missense, frameshift) that have been reported in 14 probands in 11 publications (PMIDs: 11835386, 37171481, 15136673, 28904586, 31072091, 21484434, 22312164, 35389136, 38872124, 28597716, 19158808) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence, (PMIDs: 33517449, 24532666). The zebrafish model is associated with defects in myelin development and glial cell differentiation as well as increased expression of genes in the induced stress response pathway. Protein interaction studies have shown that the subunit encoded by EIF2B3 interacts with the subunit of a previously curated gene EIF2B5. In summary, definitive evidence supports the relationship between EIF2B3 and autosomal recessive leukoencephalopathy. 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 16, 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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