Leukoencephalopathy with vanishing white matter 4

Summary

Leukoencephalopathy with vanishing white matter 4 (MONDO:0957872) is a disease caused by EIF2B4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: EIF2B4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with vanishing white matter 4
Mondo ID	MONDO:0957872
OMIM	620314
DOID	DOID:0070371
UMLS	C5830406
MedGen	1841042
GARD	0026886
Is cancer (heuristic)	no

Data availability: 19 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukoencephalopathy with vanishing white matter › leukoencephalopathy with vanishing white matter 4

Related subtypes (8): leukoencephalopathy, progressive, with ovarian failure, congenital or early infantile CACH syndrome, late infantile CACH syndrome, juvenile or adult CACH syndrome, leukoencephalopathy with vanishing white matter 1, leukoencephalopathy with vanishing white matter 2, leukoencephalopathy with vanishing white matter 3, leukoencephalopathy with vanishing white matter 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

19 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 5 pathogenic, 4 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2671575	NM_001034116.2(EIF2B4):c.1447C>T (p.Arg483Trp)	EIF2B4	Pathogenic	no assertion criteria provided
2671577	NM_001034116.2(EIF2B4):c.620T>C (p.Met207Thr)	EIF2B4	Pathogenic	no assertion criteria provided
4119	NM_001034116.2(EIF2B4):c.1191+1G>A	EIF2B4	Pathogenic	no assertion criteria provided
4120	NM_001034116.2(EIF2B4):c.683C>T (p.Ala228Val)	EIF2B4	Pathogenic	no assertion criteria provided
4121	NM_001034116.2(EIF2B4):c.1393T>C (p.Cys465Arg)	EIF2B4	Pathogenic	no assertion criteria provided
4122	NM_001034116.2(EIF2B4):c.1465T>C (p.Tyr489His)	EIF2B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420062	NM_001034116.2(EIF2B4):c.728C>T (p.Pro243Leu)	EIF2B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3767198	NM_001034116.2(EIF2B4):c.613C>G (p.Pro205Ala)	EIF2B4	Likely pathogenic	criteria provided, single submitter
4849314	NM_001034116.2(EIF2B4):c.32-1G>A	EIF2B4	Likely pathogenic	criteria provided, single submitter
4117	NM_001034116.2(EIF2B4):c.1070G>A (p.Arg357Gln)	GTF3C2-AS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203030	NM_001034116.2(EIF2B4):c.1069C>T (p.Arg357Trp)	EIF2B4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4118	NM_001034116.2(EIF2B4):c.1120C>T (p.Arg374Cys)	EIF2B4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420063	NM_001034116.2(EIF2B4):c.626G>A (p.Arg209Gln)	EIF2B4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287459	NM_001034116.2(EIF2B4):c.1399C>T (p.Arg467Trp)	GTF3C2-AS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1504593	NM_001034116.2(EIF2B4):c.955A>G (p.Ile319Val)	EIF2B4	Uncertain significance	criteria provided, single submitter
2248503	NM_001034116.2(EIF2B4):c.1411G>T (p.Val471Phe)	EIF2B4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2671576	NM_001034116.2(EIF2B4):c.1172C>A (p.Ala391Asp)	EIF2B4	Uncertain significance	criteria provided, single submitter
4292420	NM_001034116.2(EIF2B4):c.1217A>G (p.His406Arg)	EIF2B4	Uncertain significance	criteria provided, single submitter
4292633	NM_001034116.2(EIF2B4):c.1329C>G (p.Phe443Leu)	EIF2B4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
EIF2B4	Definitive	Autosomal recessive	leukoencephalopathy with vanishing white matter 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2B4	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B4	Orphanet:157716	Late infantile CACH syndrome
EIF2B4	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B4	Orphanet:99853	Ovarioleukodystrophy
EIF2B4	Orphanet:99854	Cree leukoencephalopathy

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EIF2B4	HGNC:3260	ENSG00000115211	Q9UI10	Translation initiation factor eIF2B subunit delta	gencc,clinvar
GTF3C2-AS2	HGNC:55699	ENSG00000234072		GTF3C2 antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2B4	Translation initiation factor eIF2B subunit delta	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EIF2B4	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C
GTF3C2-AS2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
left testis	1
lower esophagus mucosa	1
bone marrow cell	1
right uterine tube	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2B4	290	ubiquitous	marker	lower esophagus mucosa, body of pancreas, left testis
GTF3C2-AS2	134		yes	sural nerve, right uterine tube, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2B4	2,747
GTF3C2-AS2	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2B4	Q9UI10	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recycling of eIF2:GDP	1	1268.9×	8e-04	EIF2B4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytoplasmic translational initiation	1	1404.3×	0.005	EIF2B4
oligodendrocyte development	1	601.9×	0.005	EIF2B4
response to heat	1	421.3×	0.005	EIF2B4
ovarian follicle development	1	391.9×	0.005	EIF2B4
response to peptide hormone	1	391.9×	0.005	EIF2B4
translational initiation	1	358.6×	0.005	EIF2B4
response to glucose	1	255.3×	0.005	EIF2B4
myelination	1	251.5×	0.005	EIF2B4
regulation of translation	1	218.9×	0.005	EIF2B4
T cell receptor signaling pathway	1	151.8×	0.007	EIF2B4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2B4	0	0
GTF3C2-AS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
EIF2B4	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	EIF2B4, GTF3C2-AS2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
EIF2B4	1	—
GTF3C2-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.