Multiple epiphyseal dysplasia due to collagen 9 anomaly

Summary

Multiple epiphyseal dysplasia due to collagen 9 anomaly (MONDO:0015627) is a disease with 3 cohort genes. The dominant Reactome pathway is Collagen chain trimerization (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		59	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0003365	Arthralgia of the hip	Frequent (30-79%)
HP:0009826	Limb undergrowth	Frequent (30-79%)
HP:0012770	Reduced arm span	Frequent (30-79%)
HP:0030839	Knee pain	Frequent (30-79%)
HP:0030973	Postexertional malaise	Frequent (30-79%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002758	Osteoarthritis	Occasional (5-29%)
HP:0002812	Coxa vara	Occasional (5-29%)
HP:0002815	Abnormality of the knee	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0002970	Genu varum	Occasional (5-29%)
HP:0003028	Abnormality of the ankles	Occasional (5-29%)
HP:0003045	Abnormal patella morphology	Occasional (5-29%)
HP:0003946	Abnormality of the epiphyses of the elbow	Occasional (5-29%)
HP:0003999	Abnormality of radial epiphyses	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006055	Ulnar deviated club hands	Occasional (5-29%)
HP:0006190	Radially deviated wrists	Occasional (5-29%)
HP:0009189	Fragmentation of the metacarpal epiphyses	Occasional (5-29%)
HP:0010631	Abnormality of the epiphyses of the feet	Occasional (5-29%)
HP:0010665	Bilateral coxa valga	Occasional (5-29%)
HP:0001324	Muscle weakness	Very rare (<1-4%)
HP:0003198	Myopathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple epiphyseal dysplasia due to collagen 9 anomaly
Mondo ID	MONDO:0015627
Orphanet	166002
DOID	DOID:0070305
ICD-11	741183905
SNOMED CT	766717008
UMLS	C4707798
MedGen	1647610
GARD	0015024
Is cancer (heuristic)	no

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › connective tissue disorder › collagenopathy › multiple epiphyseal dysplasia due to collagen 9 anomaly

Related subtypes (2): disseminated eosinophilic collagen disease, type 2 collagenopathy

Subtypes (3): epiphyseal dysplasia, multiple, 2, epiphyseal dysplasia, multiple, 3, epiphyseal dysplasia, multiple, 6

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 6 · 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
COL9A1	Definitive	Autosomal dominant	epiphyseal dysplasia, multiple, 6	10
COL9A2	Definitive	Autosomal dominant	epiphyseal dysplasia, multiple, 2	9
COL9A3	Definitive	Autosomal dominant	epiphyseal dysplasia, multiple, 3	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL9A1	Orphanet:166002	Multiple epiphyseal dysplasia due to collagen 9 anomaly
COL9A1	Orphanet:250984	Autosomal recessive Stickler syndrome
COL9A2	Orphanet:166002	Multiple epiphyseal dysplasia due to collagen 9 anomaly
COL9A2	Orphanet:250984	Autosomal recessive Stickler syndrome
COL9A3	Orphanet:166002	Multiple epiphyseal dysplasia due to collagen 9 anomaly
COL9A3	Orphanet:250984	Autosomal recessive Stickler syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL9A1	HGNC:2217	ENSG00000112280	P20849	Collagen alpha-1(IX) chain	gencc
COL9A2	HGNC:2218	ENSG00000049089	Q14055	Collagen alpha-2(IX) chain	gencc
COL9A3	HGNC:2219	ENSG00000092758	Q14050	Collagen alpha-3(IX) chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL9A1	Collagen alpha-1(IX) chain	Structural component of hyaline cartilage and vitreous of the eye.
COL9A2	Collagen alpha-2(IX) chain	Structural component of hyaline cartilage and vitreous of the eye.
COL9A3	Collagen alpha-3(IX) chain	Structural component of hyaline cartilage and vitreous of the eye.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL9A1	Other/Unknown	no		Collagen, ConA-like_dom_sf, TSPN-like_N
COL9A2	Other/Unknown	no		Collagen, Collagen_superfamily
COL9A3	Other/Unknown	no		Collagen, Collagen_superfamily

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibia	3
cartilage tissue	2
ventricular zone	1
C1 segment of cervical spinal cord	1
adenohypophysis	1
inferior vagus X ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL9A1	149	broad	marker	tibia, cartilage tissue, ventricular zone
COL9A2	213	broad	marker	C1 segment of cervical spinal cord, tibia, adenohypophysis
COL9A3	218	broad	marker	tibia, cartilage tissue, inferior vagus X ganglion

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL9A1	1,488
COL9A3	1,482
COL9A2	1,419

Intra-cohort edges

A	B	Sources
COL9A1	COL9A3	string_interaction
COL9A2	COL9A3	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL9A1	P20849	5
COL9A2	Q14055	4
COL9A3	Q14050	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Collagen chain trimerization	3	259.6×	2e-07	COL9A1, COL9A2, COL9A3
Signaling by PDGF	3	253.8×	2e-07	COL9A1, COL9A2, COL9A3
NCAM1 interactions	3	248.3×	2e-07	COL9A1, COL9A2, COL9A3
Assembly of collagen fibrils and other multimeric structures	3	200.3×	2e-07	COL9A1, COL9A2, COL9A3
Collagen degradation	3	175.7×	3e-07	COL9A1, COL9A2, COL9A3
Collagen biosynthesis and modifying enzymes	3	170.4×	3e-07	COL9A1, COL9A2, COL9A3
ECM proteoglycans	3	150.3×	3e-07	COL9A1, COL9A2, COL9A3
Integrin cell surface interactions	3	134.3×	4e-07	COL9A1, COL9A2, COL9A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
animal organ morphogenesis	1	95.8×	0.016	COL9A1
skeletal system development	1	62.9×	0.016	COL9A2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
COL9A1	0	0
COL9A2	0	0
COL9A3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	COL9A1, COL9A2, COL9A3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL9A1	0	—
COL9A2	0	—
COL9A3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.