EIF2B2

Inheritance Pattern: AR

Disease ID:MONDO:0020506

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0957870

Submitter: ClinGen

EIF2B2 was first associated with autosomal recessive leukoencephalopathy with vanishing white matter in 2001 (Leegwater., PMID: 11704758). Individuals with EIF2B2-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 2 (OMIM:606454, MONDO:0957870). Twelve variants (missense, nonsense, frameshift) that have been reported in 10 probands in 5 publications (PMIDs: 15136673, 29700822, 11704758, 25843247, 31438897) 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: 33300869, 24532666). The zebrafish model is associated with impaired motor behavior and abnormal CNS development. Protein interaction studies have shown that the subunit encoded by EIF2B2 interacts with the subunit of a previously curated gene EIF2B5. In summary, definitive evidence supports the relationship between EIF2B2 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).

Inheritance Pattern: AR

Disease ID:MONDO:0957870

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0800448

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0011380

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0011380

Submitter: Illumina

The EIF2B2 gene is located on chromosome 14 at 14q24.3 and encodes eukaryotic translation initiation factor 2B subunit beta. EIF2B2 forms a protein complex with four other EIF2B subunits and plays an important role in the initiation of mRNA translation by activating protein synthesis initiation factor 2 through its guanine nucleotide exchange factor activity. EIF2B2 was first reported in relation to leukoencephalopathy with vanishing white matter in 2001 (11704758: Leegwater et al. 2001). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 12 variants, including missense and loss of function variants have been reported in at least eight probands from four publications (11704758: Leegwater et al. 2001; 14566705: van der Knapp et al. 2003; 15054402: Fogli et al. 2004; 21484434: Matsukawa et al. 2011). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. Clinical evidence indicates that loss of function is the mechanism of disease. This gene-disease association is supported by the biochemical function of EIF2B2 and other genes in the EIF2B complex are associated with the disease (20301435: van der Knaap et al. 2019). Co-immunoprecipitation experiments demonstrate an interaction between EIF2B2 and all four of the other EIF2B subunits (14993275: Richardson et al. 2004). In vitro functional analyses of patient-identified missense variants suggest loss of function, including disruption of interactions with other subunits and impaired translation (14993275: Richardson et al. 2004). In summary, the EIF2B2 gene is definitively associated with leukoencephalopathy with vanishing white matter.

Inheritance Pattern: AR

Disease ID:MONDO:0020507

Submitter: Labcorp Genetics (formerly Invitae)