Wagner disease

Summary

Wagner disease (MONDO:0007740) is a disease caused by VCAN (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VCAN (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 136
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000533	Chorioretinal atrophy	Frequent (30-79%)
HP:0000541	Retinal detachment	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000580	Pigmentary retinopathy	Frequent (30-79%)
HP:0000662	Nyctalopia	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0007819	Presenile cataracts	Frequent (30-79%)
HP:0030466	Abnormal full-field electroretinogram	Frequent (30-79%)
HP:0030663	Optically empty vitreous	Frequent (30-79%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0025007	Ectopic fovea	Occasional (5-29%)
HP:0012122	Anterior uveitis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Wagner disease
Mondo ID	MONDO:0007740
MeSH	C536075
OMIM	143200
Orphanet	898
ICD-11	780893571
SNOMED CT	232064001
UMLS	C1840452
MedGen	326741
GARD	0007871
MedDRA	10063383
Is cancer (heuristic)	no

Also known as: dominant hyaloideoretinal dystrophy of Wagner · ERVR · VCAN-related vitreoretinopathy · vitreoretinal degeneration, Wagner type · Wagner disease · Wagner disease (formerly) · Wagner syndrome · Wagner syndrome type 1 · Wagner vitreoretinopathy · WGN1 · WGVRP

Data availability: 136 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › vitreous body disorder › vitreous disorder › vitreous syneresis › vitreoretinal degeneration › Wagner disease

Related subtypes (8): snowflake vitreoretinal degeneration, X-linked retinoschisis, Stickler syndrome, exudative vitreoretinopathy, enhanced S-cone syndrome, CAPN5-related vitreoretinopathy, BEST1-related vitreoretinochoroidopathy, Knobloch syndrome

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

136 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 25 conflicting classifications of pathogenicity, 24 benign, 15 benign/likely benign, 11 pathogenic, 4 likely pathogenic, 3 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
17494	NM_004385.5(VCAN):c.4004-2A>G	VCAN	Pathogenic	criteria provided, multiple submitters, no conflicts
21405	NM_004385.5(VCAN):c.4004-1G>A	VCAN	Pathogenic	criteria provided, multiple submitters, no conflicts
21408	NM_004385.5(VCAN):c.9265+1G>A	VCAN	Pathogenic	criteria provided, single submitter
219011	NM_004385.5(VCAN):c.4004-1G>T	VCAN	Pathogenic	criteria provided, single submitter
41879	NM_004385.5(VCAN):c.4004-1G>C	VCAN	Pathogenic	no assertion criteria provided
21406	NM_004385.5(VCAN):c.4004-5T>A	VCAN-AS1	Pathogenic	no assertion criteria provided
21407	NM_004385.5(VCAN):c.4004-5T>C	VCAN-AS1	Pathogenic	criteria provided, single submitter
41877	NM_004385.5(VCAN):c.4004-2A>T	VCAN-AS1	Pathogenic	criteria provided, single submitter
41878	NM_004385.5(VCAN):c.9265+2T>A	VCAN-AS1	Pathogenic	no assertion criteria provided
813123	NM_004385.5(VCAN):c.4004-2A>C	VCAN-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
859925	NM_004385.5(VCAN):c.9265+1G>C	VCAN-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
219010	NM_004385.5(VCAN):c.9265+1G>T	VCAN	Likely pathogenic	criteria provided, single submitter
3255113	NM_004385.5(VCAN):c.9265G>C (p.Gly3089Arg)	VCAN	Likely pathogenic	criteria provided, single submitter
3775172	NM_004385.5(VCAN):c.3455C>A (p.Ser1152Ter)	VCAN	Likely pathogenic	criteria provided, single submitter
4814165	NM_004385.5(VCAN):c.1011del (p.Asp338fs)	VCAN	Likely pathogenic	criteria provided, single submitter
1528857	NM_004385.5(VCAN):c.3540A>G (p.Leu1180=)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167819	NM_004385.5(VCAN):c.927T>C (p.Thr309=)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
843872	NM_004385.5(VCAN):c.157C>T (p.Pro53Ser)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
848210	NM_004385.5(VCAN):c.221A>G (p.Asn74Ser)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
860846	NM_004385.5(VCAN):c.160C>T (p.Pro54Ser)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903795	NM_004385.5(VCAN):c.1369G>A (p.Glu457Lys)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903868	NM_004385.5(VCAN):c.2668G>T (p.Gly890Cys)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904378	NM_004385.5(VCAN):c.9619A>G (p.Ile3207Val)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904379	NM_004385.5(VCAN):c.9758A>G (p.Asn3253Ser)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905032	NM_004385.5(VCAN):c.8474C>T (p.Pro2825Leu)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906080	NM_004385.5(VCAN):c.375G>A (p.Ala125=)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906146	NM_004385.5(VCAN):c.1009C>G (p.Pro337Ala)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907149	NM_004385.5(VCAN):c.1127A>C (p.Asp376Ala)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907150	NM_004385.5(VCAN):c.1240G>A (p.Ala414Thr)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907452	NM_004385.5(VCAN):c.6322C>G (p.Gln2108Glu)	VCAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
VCAN	Definitive	Autosomal dominant	Wagner disease	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VCAN	Orphanet:898	Wagner disease

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
VCAN	HGNC:2464	ENSG00000038427	P13611	Versican core protein	gencc,clinvar
VCAN-AS1	HGNC:40163	ENSG00000249835		VCAN antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VCAN	Versican core protein	May play a role in intercellular signaling and in connecting cells with the extracellular matrix.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Complement	1	134.0×	0.015
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VCAN	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, Link_dom
VCAN-AS1	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
leukocyte	1
monocyte	1
mononuclear cell	1
calcaneal tendon	1
granulocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VCAN	293	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
VCAN-AS1	126		yes	ventricular zone, granulocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCAN	2,806
VCAN-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VCAN	P13611

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective CHST3 causes SEDCJD	1	1427.5×	0.003	VCAN
Defective CHST14 causes EDS, musculocontractural type	1	1427.5×	0.003	VCAN
Defective CHSY1 causes TPBS	1	1427.5×	0.003	VCAN
DS-GAG biosynthesis	1	951.7×	0.003	VCAN
Defective B4GALT7 causes EDS, progeroid type	1	571.0×	0.003	VCAN
Defective B3GAT3 causes JDSSDHD	1	571.0×	0.003	VCAN
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	571.0×	0.003	VCAN
CS-GAG biosynthesis	1	543.8×	0.003	VCAN
CS/DS degradation	1	543.8×	0.003	VCAN
Glycosaminoglycan-protein linkage region biosynthesis	1	393.8×	0.003	VCAN
ECM proteoglycans	1	150.3×	0.008	VCAN
Post-translational protein phosphorylation	1	100.2×	0.011	VCAN
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	VCAN

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
cell recognition	1	1872.4×	0.002	VCAN
glial cell migration	1	1404.3×	0.002	VCAN
skeletal system development	1	125.8×	0.010	VCAN
osteoblast differentiation	1	121.2×	0.010	VCAN
central nervous system development	1	115.4×	0.010	VCAN
cell adhesion	1	37.5×	0.027	VCAN

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
VCAN	0	0
VCAN-AS1	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	1	VCAN
E	Difficult family or no structure, no drug	1	VCAN-AS1

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)
VCAN	0	—
VCAN-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.