Hypomyelinating leukodystrophy 12

Summary

Hypomyelinating leukodystrophy 12 (MONDO:0014732) is a disease caused by VPS11 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VPS11 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0100704	Cerebral visual impairment	Very frequent (80-99%)
HP:0002518	Abnormal periventricular white matter morphology	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0007204	Diffuse white matter abnormalities	Frequent (30-79%)
HP:0007301	Oromotor apraxia	Frequent (30-79%)
HP:0012332	Abnormal autonomic nervous system physiology	Frequent (30-79%)
HP:0000011	Neurogenic bladder	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002188	Delayed CNS myelination	Frequent (30-79%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0000280	Coarse facial features	Excluded (0%)
HP:0001433	Hepatosplenomegaly	Excluded (0%)
HP:0001272	Cerebellar atrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 12
Mondo ID	MONDO:0014732
OMIM	616683
Orphanet	466934
DOID	DOID:0060796
UMLS	C4225247
MedGen	905068
GARD	0017837
Is cancer (heuristic)	no

Also known as: HLD12 · hypomyelinating leukodystrophy type 12 · leukodystrophy caused by mutation in VPS11 · leukodystrophy, hypomyelinating, 12 · leukodystrophy, hypomyelinating, type 12 · VPS11 leukodystrophy · VPS11-related autosomal recessive hypomyelinating leukoencephalopathy

Data availability: 20 ClinVar variants · 3 GenCC gene-disease records.

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 › hypomyelinating leukodystrophy 12

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

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

20 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 6 benign, 2 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1326861	NM_021729.6(VPS11):c.1158_1184del (p.Leu387_Gly395del)	VPS11	Pathogenic	no assertion criteria provided
218366	NM_021729.6(VPS11):c.2536T>G (p.Cys846Gly)	VPS11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029819	NM_021729.6(VPS11):c.367G>A (p.Gly123Ser)	VPS11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
790365	NM_021729.6(VPS11):c.2078T>C (p.Met693Thr)	VPS11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032881	NM_021729.6(VPS11):c.1085A>T (p.Glu362Val)	VPS11	Uncertain significance	criteria provided, single submitter
1032882	NM_021729.6(VPS11):c.2384G>A (p.Arg795Gln)	VPS11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032883	NM_021729.6(VPS11):c.2806C>T (p.His936Tyr)	VPS11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1305992	NM_021729.6(VPS11):c.1640G>A (p.Arg547His)	VPS11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806086	NM_021729.6(VPS11):c.190A>C (p.Met64Leu)	VPS11	Uncertain significance	criteria provided, single submitter
1806320	NM_021729.6(VPS11):c.2440C>T (p.Pro814Ser)	VPS11	Uncertain significance	criteria provided, single submitter
2441897	NM_021729.6(VPS11):c.976G>A (p.Val326Ile)	VPS11	Uncertain significance	criteria provided, single submitter
2572398	NM_021729.6(VPS11):c.187+70_187+73del	VPS11	Uncertain significance	criteria provided, single submitter
635068	NM_021729.6(VPS11):c.2557A>G (p.Ser853Gly)	VPS11	Uncertain significance	criteria provided, single submitter
976215	NM_021729.6(VPS11):c.2615_2620del (p.Arg872_Ala873del)	VPS11	Uncertain significance	criteria provided, single submitter
1164301	NM_021729.6(VPS11):c.1266C>T (p.Tyr422=)	VPS11	Benign	criteria provided, multiple submitters, no conflicts
1165119	NM_021729.6(VPS11):c.1238+14C>T	VPS11	Benign	criteria provided, multiple submitters, no conflicts
1168494	NM_021729.6(VPS11):c.486C>G (p.Gly162=)	VPS11	Benign	criteria provided, multiple submitters, no conflicts
1301765	NM_021729.6(VPS11):c.187+159A>G	VPS11	Benign	criteria provided, multiple submitters, no conflicts
1684211	NM_021729.6(VPS11):c.1977C>T (p.Phe659=)	VPS11	Benign	criteria provided, single submitter
1684212	NM_021729.6(VPS11):c.*38A>G	VPS11	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
VPS11	Strong	Autosomal recessive	hypomyelinating leukodystrophy 12	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS11	Orphanet:466934	VPS11-related autosomal recessive hypomyelinating leukodystrophy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS11	HGNC:14583	ENSG00000160695	Q9H270	Vacuolar protein sorting-associated protein 11 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS11	Vacuolar protein sorting-associated protein 11 homolog	Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS11	Transcription factor	no		Clathrin_H-chain/VPS_repeat, Znf_RING, TPR-like_helical_dom_sf

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
pituitary gland	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS11	134	ubiquitous	marker	prefrontal cortex, pituitary gland, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS11	1,773

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS11	Q9H270	79.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
SARS-CoV-2 modulates autophagy	1	1038.2×	1e-03	VPS11

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
organelle fusion	1	4213.0×	0.002	VPS11
regulation of organelle assembly	1	3370.4×	0.002	VPS11
positive regulation of early endosome to late endosome transport	1	1872.4×	0.002	VPS11
vacuole organization	1	1532.0×	0.002	VPS11
regulation of SNARE complex assembly	1	1296.3×	0.002	VPS11
negative regulation of intracellular estrogen receptor signaling pathway	1	1123.5×	0.002	VPS11
endosomal vesicle fusion	1	1123.5×	0.002	VPS11
obsolete vesicle docking involved in exocytosis	1	674.1×	0.003	VPS11
obsolete positive regulation of protein targeting to mitochondrion	1	495.6×	0.004	VPS11
endosome organization	1	374.5×	0.004	VPS11
endosome to lysosome transport	1	337.0×	0.004	VPS11
positive regulation of protein catabolic process	1	203.0×	0.007	VPS11
regulation of protein stability	1	125.8×	0.010	VPS11
autophagy	1	110.1×	0.010	VPS11
intracellular protein transport	1	64.8×	0.016	VPS11
protein ubiquitination	1	41.4×	0.024	VPS11

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS11	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	VPS11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.