Multiple epiphyseal dysplasia type 5

Summary

Multiple epiphyseal dysplasia type 5 (MONDO:0011765) is a disease caused by MATN3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MATN3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 81
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0001385	Hip dysplasia	Very frequent (80-99%)
HP:0008828	Delayed proximal femoral epiphyseal ossification	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001384	Abnormality of the hip joint	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0002970	Genu varum	Frequent (30-79%)
HP:0003088	Premature osteoarthritis	Frequent (30-79%)
HP:0003502	Mild short stature	Frequent (30-79%)
HP:0003839	Abnormality of upper limb epiphysis morphology	Frequent (30-79%)
HP:0010631	Abnormality of the epiphyses of the feet	Frequent (30-79%)
HP:0030839	Knee pain	Frequent (30-79%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0003170	Abnormality of the acetabulum	Occasional (5-29%)
HP:0003184	Decreased hip abduction	Occasional (5-29%)
HP:0003365	Arthralgia of the hip	Occasional (5-29%)
HP:0004268	Osteoarthritis of the small joints of the hand	Occasional (5-29%)
HP:0005743	Avascular necrosis of the capital femoral epiphysis	Occasional (5-29%)
HP:0005877	Multiple small vertebral fractures	Occasional (5-29%)
HP:0008419	Intervertebral disc degeneration	Occasional (5-29%)
HP:0008800	Limited hip movement	Occasional (5-29%)
HP:0030840	Ankle pain	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0003418	Back pain	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple epiphyseal dysplasia type 5
Mondo ID	MONDO:0011765
MeSH	C535505
OMIM	607078
Orphanet	93311
DOID	DOID:0070299
ICD-11	537678813
SNOMED CT	715674008
UMLS	C1846843
MedGen	335542
GARD	0009794
Is cancer (heuristic)	no

Also known as: BHMED · bilateral hereditary micro-epiphyseal dysplasia · EDM5 · epiphyseal dysplasia multiple 5 · epiphyseal dysplasia, multiple, 5 · epiphyseal dysplasia, multiple, type 5 · MATN3 multiple epiphyseal dysplasia (disease) · MED5 · multiple epiphyseal dysplasia (disease) caused by mutation in MATN3 · multiple epiphyseal dysplasia 5 · multiple epiphyseal dysplasia, MATN3 related · Polyepiphyseal dysplasia type 5

Data availability: 81 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › multiple epiphyseal dysplasia › multiple epiphyseal dysplasia type 5

Related subtypes (9): multiple epiphyseal dysplasia type 1, multiple epiphyseal dysplasia, Beighton type, multiple epiphyseal dysplasia type 4, multiple epiphyseal dysplasia, Lowry type, multiple epiphyseal dysplasia, Al-Gazali type, multiple epiphyseal dysplasia, with severe proximal femoral dysplasia, multiple epiphyseal dysplasia, with miniepiphyses, multiple epiphyseal dysplasia due to collagen 9 anomaly, epiphyseal dysplasia, multiple, 7

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

81 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 13 conflicting classifications of pathogenicity, 9 benign, 4 pathogenic, 3 benign/likely benign, 2 likely pathogenic, 2 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299496	NC_000002.12:g.19998776_20009244dup	MATN3	Pathogenic	no assertion criteria provided
65664	NM_002381.5(MATN3):c.359C>T (p.Thr120Met)	MATN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7540	NM_002381.5(MATN3):c.581T>A (p.Val194Asp)	MATN3	Pathogenic	no assertion criteria provided
7541	NM_002381.5(MATN3):c.361C>T (p.Arg121Trp)	MATN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7543	NM_002381.5(MATN3):c.656C>A (p.Ala219Asp)	MATN3	Pathogenic	criteria provided, single submitter
7546	NM_002381.5(MATN3):c.382G>C (p.Ala128Pro)	MATN3	Pathogenic	no assertion criteria provided
1683458	NM_002381.5(MATN3):c.368C>T (p.Ala123Val)	MATN3	Likely pathogenic	criteria provided, single submitter
560181	NM_002381.5(MATN3):c.224-2153_1168+903dup	MATN3	Likely pathogenic	criteria provided, single submitter
196341	NM_002381.5(MATN3):c.792G>A (p.Ala264=)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283602	NM_002381.5(MATN3):c.62T>G (p.Leu21Arg)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333423	NM_002381.5(MATN3):c.664G>A (p.Val222Met)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333426	NM_002381.5(MATN3):c.349C>T (p.Pro117Ser)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333427	NM_002381.5(MATN3):c.330C>T (p.Ile110=)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
720237	NM_002381.5(MATN3):c.223+8C>A	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
739482	NM_002381.5(MATN3):c.90C>T (p.Pro30=)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
843499	NM_002381.5(MATN3):c.653A>G (p.Tyr218Cys)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895350	NM_002381.5(MATN3):c.1065T>C (p.Gly355=)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896761	NM_002381.5(MATN3):c.822G>A (p.Gln274=)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897313	NM_002381.5(MATN3):c.275G>A (p.Arg92His)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898414	NM_002381.5(MATN3):c.733G>A (p.Val245Met)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898677	NM_002381.5(MATN3):c.150C>T (p.Arg50=)	MATN3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3891633	NC_000008.11:g.20335399_20335401del		Uncertain significance	criteria provided, single submitter
1228375	NM_002381.5(MATN3):c.477C>T (p.Gly159=)	MATN3	Uncertain significance	criteria provided, single submitter
1329477	NM_002381.5(MATN3):c.284G>A (p.Arg95Gln)	MATN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675216	NM_002381.5(MATN3):c.693G>C (p.Lys231Asn)	MATN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2156741	NM_002381.5(MATN3):c.752T>C (p.Ile251Thr)	MATN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2580217	NM_002381.5(MATN3):c.302A>G (p.Lys101Arg)	MATN3	Uncertain significance	criteria provided, single submitter
2731695	NM_002381.5(MATN3):c.1324A>G (p.Thr442Ala)	MATN3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065484	NM_002381.5(MATN3):c.572C>A (p.Ala191Asp)	MATN3	Uncertain significance	criteria provided, single submitter
3068089	NM_002381.5(MATN3):c.709C>T (p.Pro237Ser)	MATN3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
MATN3	Definitive	Autosomal dominant	multiple epiphyseal dysplasia type 5	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MATN3	Orphanet:156728	Spondyloepimetaphyseal dysplasia, matrilin-3 type
MATN3	Orphanet:93311	Multiple epiphyseal dysplasia type 5

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
MATN3	HGNC:6909	ENSG00000132031	O15232	Matrilin-3	gencc,clinvar
WDR35-DT	HGNC:55818	ENSG00000227210		WDR35 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MATN3	Matrilin-3	Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks.

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)
MATN3	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, VWF_A
WDR35-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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
primordial germ cell in gonad	2
cartilage tissue	1
tibia	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MATN3	167	broad	yes	tibia, cartilage tissue, primordial germ cell in gonad
WDR35-DT	141		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MATN3	1,918
WDR35-DT	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MATN3	O15232	79.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
ECM proteoglycans	1	150.3×	0.023	MATN3
Post-translational protein phosphorylation	1	100.2×	0.023	MATN3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.023	MATN3
Extracellular matrix organization	1	63.1×	0.024	MATN3
Post-translational protein modification	1	19.2×	0.063	MATN3
Metabolism of proteins	1	12.4×	0.081	MATN3

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
cartilage development	1	251.5×	0.008	MATN3
skeletal system development	1	125.8×	0.008	MATN3
extracellular matrix organization	1	122.1×	0.008	MATN3

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
MATN3	0	0
WDR35-DT	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	2	MATN3, WDR35-DT

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)
MATN3	0	—
WDR35-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.