Multiple epiphyseal dysplasia type 1

Summary

Multiple epiphyseal dysplasia type 1 (MONDO:0007561) is a disease caused by COMP (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: COMP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 117
• Phenotypes (HPO): 21

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001385	Hip dysplasia	Frequent (30-79%)
HP:0003026	Short long bone	Frequent (30-79%)
HP:0003365	Arthralgia of the hip	Frequent (30-79%)
HP:0030839	Knee pain	Frequent (30-79%)
HP:0030973	Postexertional malaise	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002663	Delayed epiphyseal ossification	Occasional (5-29%)
HP:0002758	Osteoarthritis	Occasional (5-29%)
HP:0003170	Abnormality of the acetabulum	Occasional (5-29%)
HP:0003498	Disproportionate short stature	Occasional (5-29%)
HP:0006094	Finger joint hypermobility	Occasional (5-29%)
HP:0030840	Ankle pain	Occasional (5-29%)
HP:0045086	Knee joint hypermobility	Occasional (5-29%)
HP:0001156	Brachydactyly	Excluded (0%)
HP:0002812	Coxa vara	Very rare (<1-4%)
HP:0002857	Genu valgum	Very rare (<1-4%)
HP:0002970	Genu varum	Very rare (<1-4%)
HP:0005743	Avascular necrosis of the capital femoral epiphysis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple epiphyseal dysplasia type 1
Mondo ID	MONDO:0007561
OMIM	132400
Orphanet	93308
DOID	DOID:0070303
ICD-11	2130489957
SNOMED CT	715673002
UMLS	C1838280
MedGen	325376
GARD	0002180
Is cancer (heuristic)	no

Also known as: COMP multiple epiphyseal dysplasia (disease) · EDM1 · epiphyseal dysplasia multiple 1 · epiphyseal dysplasia, multiple, 1 · epiphyseal dysplasia, multiple, type 1 · MED1 · multiple epiphyseal dysplasia (disease) caused by mutation in COMP · multiple epiphyseal dysplasia 1 · multiple epiphyseal dysplasia COMP-related · Polyepiphyseal dysplasia type 1

Data availability: 117 ClinVar variants · 3 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 1

Related subtypes (9): multiple epiphyseal dysplasia, Beighton type, multiple epiphyseal dysplasia type 4, multiple epiphyseal dysplasia, Lowry type, multiple epiphyseal dysplasia type 5, 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

117 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 20 likely pathogenic, 16 conflicting classifications of pathogenicity, 13 benign/likely benign, 10 pathogenic/likely pathogenic, 9 benign, 7 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332753	NM_000088.4(COL1A1):c.2029-1G>T	COL1A1	Pathogenic	criteria provided, single submitter
1066197	NM_000095.3(COMP):c.1317C>G (p.Asp439Glu)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332822	NM_000095.3(COMP):c.976G>A (p.Asp326Asn)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404680	NM_000095.3(COMP):c.1114GAC[2] (p.Asp374del)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709017	NM_000095.3(COMP):c.1665C>G (p.Asn555Lys)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066042	NM_000095.3(COMP):c.1359del (p.Asn453fs)	COMP	Pathogenic	no assertion criteria provided
40988	NM_000095.3(COMP):c.1405GAC[4] (p.Asp473del)	COMP	Pathogenic	criteria provided, multiple submitters, no conflicts
40994	NM_000095.3(COMP):c.1754C>G (p.Thr585Arg)	COMP	Pathogenic	criteria provided, single submitter
4819371	NM_000095.3(COMP):c.1424A>G (p.Asp475Gly)	COMP	Pathogenic	criteria provided, single submitter
807400	NM_000095.3(COMP):c.1153G>T (p.Asp385Tyr)	COMP	Pathogenic	criteria provided, single submitter
818218	NM_000095.3(COMP):c.874T>C (p.Cys292Arg)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9189	NM_000095.3(COMP):c.1569C>G (p.Asn523Lys)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9193	NM_000095.3(COMP):c.1405GAC[6] (p.Asp473dup)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9194	NM_000095.3(COMP):c.2156G>A (p.Gly719Asp)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9197	NM_000095.3(COMP):c.2223dup (p.Asn742fs)	COMP	Pathogenic	no assertion criteria provided
9198	NM_000095.3(COMP):c.2152C>T (p.Arg718Trp)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988351	NM_000095.3(COMP):c.1153G>A (p.Asp385Asn)	COMP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299574	NM_000095.3(COMP):c.1228T>G (p.Cys410Gly)	COMP	Likely pathogenic	criteria provided, single submitter
1327423	NM_000095.3(COMP):c.1501G>A (p.Gly501Ser)	COMP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339213	NM_000095.3(COMP):c.1201G>T (p.Asp401Tyr)	COMP	Likely pathogenic	criteria provided, single submitter
1676245	NM_000095.3(COMP):c.1126G>A (p.Asp376Asn)	COMP	Likely pathogenic	criteria provided, single submitter
1683446	NM_000095.3(COMP):c.2170dup (p.Val724fs)	COMP	Likely pathogenic	criteria provided, single submitter
1683453	NM_000095.3(COMP):c.1367A>C (p.Gln456Pro)	COMP	Likely pathogenic	criteria provided, single submitter
1685287	NM_000095.3(COMP):c.949G>T (p.Asp317Tyr)	COMP	Likely pathogenic	criteria provided, single submitter
2412784	NM_000095.3(COMP):c.818A>G (p.Asp273Gly)	COMP	Likely pathogenic	criteria provided, single submitter
3065273	NM_000095.3(COMP):c.1586C>A (p.Thr529Asn)	COMP	Likely pathogenic	criteria provided, single submitter
3069181	NM_000095.3(COMP):c.1303G>C (p.Asp435His)	COMP	Likely pathogenic	criteria provided, single submitter
4072050	NM_000095.3(COMP):c.1454G>T (p.Arg485Leu)	COMP	Likely pathogenic	criteria provided, single submitter
438839	NM_000095.3(COMP):c.1126G>T (p.Asp376Tyr)	COMP	Likely pathogenic	criteria provided, single submitter
449474	NM_000095.3(COMP):c.1195G>A (p.Asp399Asn)	COMP	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 12 · 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
COMP	Strong	Autosomal dominant	multiple epiphyseal dysplasia type 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COMP	Orphanet:750	Pseudoachondroplasia
COMP	Orphanet:93308	Multiple epiphyseal dysplasia type 1
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COMP	HGNC:2227	ENSG00000105664	P49747	Cartilage oligomeric matrix protein	gencc,clinvar
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COMP	Cartilage oligomeric matrix protein	Plays a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin.
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).

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)
COMP	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, Thrombospondin_3-like_rpt
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cartilage tissue	1
tibia	1
periodontal ligament	1
skin of hip	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COMP	195	broad	marker	tibia, cartilage tissue, calcaneal tendon
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
COMP	2,205

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL1A1	P02452	14
COMP	P49747	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ECM proteoglycans	2	150.3×	7e-04	COMP, COL1A1
Integrin cell surface interactions	2	134.3×	7e-04	COMP, COL1A1
Defective VWF binding to collagen type I	1	1903.3×	0.004	COL1A1
Enhanced cleavage of VWF variant by ADAMTS13	1	1427.5×	0.004	COL1A1
Defective VWF cleavage by ADAMTS13 variant	1	1427.5×	0.004	COL1A1
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	815.7×	0.005	COL1A1
Defective binding of VWF variant to GPIb:IX:V	1	815.7×	0.005	COL1A1
GP1b-IX-V activation signalling	1	475.8×	0.007	COL1A1
Anchoring fibril formation	1	380.7×	0.007	COL1A1
Platelet Adhesion to exposed collagen	1	335.9×	0.007	COL1A1
Scavenging by Class A Receptors	1	300.5×	0.007	COL1A1
Fibronectin matrix formation	1	285.5×	0.007	COL1A1
Crosslinking of collagen fibrils	1	285.5×	0.007	COL1A1
RUNX2 regulates osteoblast differentiation	1	228.4×	0.008	COL1A1
Platelet Aggregation (Plug Formation)	1	219.6×	0.008	COL1A1
Syndecan interactions	1	211.5×	0.008	COL1A1
MET activates PTK2 signaling	1	190.3×	0.008	COL1A1
GPVI-mediated activation cascade	1	154.3×	0.009	COL1A1
Collagen chain trimerization	1	129.8×	0.011	COL1A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.011	COL1A1
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.012	COL1A1
Collagen degradation	1	87.8×	0.013	COL1A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.013	COL1A1
Non-integrin membrane-ECM interactions	1	77.2×	0.014	COL1A1
Cell surface interactions at the vascular wall	1	47.6×	0.022	COL1A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.023	COL1A1

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
collagen fibril organization	2	224.7×	0.001	COMP, COL1A1
cellular response to vitamin E	1	8426.0×	0.002	COL1A1
negative regulation of hemostasis	1	8426.0×	0.002	COMP
skeletal system development	2	125.8×	0.002	COMP, COL1A1
cellular response to fluoride	1	4213.0×	0.003	COL1A1
tooth mineralization	1	2808.7×	0.004	COL1A1
tendon development	1	2106.5×	0.004	COMP
vascular associated smooth muscle contraction	1	1685.2×	0.004	COMP
cellular response to acetaldehyde	1	1685.2×	0.004	COL1A1
cartilage homeostasis	1	1685.2×	0.004	COMP
intramembranous ossification	1	1404.3×	0.004	COL1A1
musculoskeletal movement	1	1404.3×	0.004	COMP
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.004	COL1A1
growth plate cartilage development	1	1053.2×	0.004	COMP
bone trabecula formation	1	1053.2×	0.004	COL1A1
positive regulation of chondrocyte proliferation	1	936.2×	0.005	COMP
vascular associated smooth muscle cell development	1	842.6×	0.005	COMP
skin morphogenesis	1	702.2×	0.005	COL1A1
collagen-activated tyrosine kinase receptor signaling pathway	1	648.1×	0.006	COL1A1
response to hyperoxia	1	561.7×	0.006	COL1A1
negative regulation of cell-substrate adhesion	1	526.6×	0.006	COL1A1
collagen biosynthetic process	1	526.6×	0.006	COL1A1
chondrocyte proliferation	1	526.6×	0.006	COMP
chondrocyte development	1	468.1×	0.006	COMP
response to steroid hormone	1	421.3×	0.006	COL1A1
regulation of bone mineralization	1	366.4×	0.007	COMP
artery morphogenesis	1	337.0×	0.007	COMP
endochondral ossification	1	271.8×	0.009	COL1A1
cellular response to fibroblast growth factor stimulus	1	271.8×	0.009	COL1A1
response to cAMP	1	255.3×	0.009	COL1A1

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
COMP	0	0
COL1A1	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
COL1A1	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	COMP, COL1A1

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)
COMP	0	—
COL1A1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.