metaphyseal chondrodysplasia, Spahr type

Summary

metaphyseal chondrodysplasia, Spahr type (MONDO:0009597) is a disease caused by MMP13 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MMP13 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 12
• Phenotypes (HPO): 17

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)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001385	Hip dysplasia	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0002970	Genu varum	Very frequent (80-99%)
HP:0003307	Hyperlordosis	Very frequent (80-99%)
HP:0003498	Disproportionate short stature	Very frequent (80-99%)
HP:0004349	Reduced bone mineral density	Very frequent (80-99%)
HP:0005871	Metaphyseal chondrodysplasia	Very frequent (80-99%)
HP:0006385	Short lower limbs	Very frequent (80-99%)
HP:0006409	Progressive leg bowing	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0100255	Metaphyseal dysplasia	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	metaphyseal chondrodysplasia, Spahr type
Mondo ID	MONDO:0009597
MeSH	C537353
OMIM	250400
Orphanet	2501
ICD-11	1856002752
SNOMED CT	254084008
UMLS	C0432225
MedGen	140928
GARD	0003563
Is cancer (heuristic)	no

Also known as: MDST · metaphyseal chondrodysplasia Spahr type · metaphyseal chondrodysplasia, Spahr type · metaphyseal dysplasia, Spahr type · Spahr type metaphyseal chondrodysplasia

Data availability: 12 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 › metaphyseal chondrodysplasia, Spahr type

Related subtypes (49): atelosteogenesis, midface dysplasia, Kashin-Beck disease, achondroplasia, Boomerang dysplasia, campomelic dysplasia, cleidocranial dysplasia 1, Leri-Weill dyschondrosteosis, hypochondroplasia, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, Kniest dysplasia, pseudoachondroplasia, ulna metaphyseal dysplasia syndrome, acheiropody, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, bone dysplasia, lethal Holmgren type, cleidocranial dysplasia, recessive form, diastrophic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, lethal Kniest-like dysplasia, metaphyseal chondrodysplasia, Kaitila type, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, pycnodysostosis, pyknoachondrogenesis, Pyle disease, schneckenbecken dysplasia, mesomelia-synostoses syndrome, lethal chondrodysplasia, Seller type, acrocapitofemoral dysplasia, brachyolmia, Desbuquois dysplasia, fibrochondrogenesis, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, thanatophoric dysplasia, Blount disease, osteogenesis imperfecta, achondrogenesis, acromesomelic dysplasia, neonatal osteosclerotic dysplasia, Akaba Hayasaka syndrome, Fairbank disease, mesomelic dysplasia, spondyloepimetaphyseal dysplasia, cleidocranial dysplasia 2, arterial tortuosity-bone fragility syndrome, linkeropathy

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

12 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 2 benign/likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
183688	NM_002427.4(MMP13):c.325C>T (p.Arg109Ter)	LOC126861318	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9445	NM_002427.4(MMP13):c.272T>C (p.Met91Thr)	LOC126861318	Pathogenic	criteria provided, multiple submitters, no conflicts
183687	NM_002427.4(MMP13):c.619T>G (p.Trp207Gly)	MMP13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9446	NM_002427.4(MMP13):c.694C>A (p.His232Asn)	MMP13	Pathogenic	no assertion criteria provided
1445998	NM_002427.4(MMP13):c.1384G>A (p.Val462Ile)	MMP13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301974	NM_002427.4(MMP13):c.1372C>T (p.Arg458Cys)	MMP13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930588	NM_002427.4(MMP13):c.206G>T (p.Arg69Leu)	LOC126861318	Uncertain significance	criteria provided, single submitter
3779879	NM_002427.4(MMP13):c.917+2T>A	MMP13	Uncertain significance	criteria provided, single submitter
3891700	NM_002427.4(MMP13):c.893G>A (p.Gly298Glu)	MMP13	Uncertain significance	criteria provided, single submitter
548485	NM_002427.4(MMP13):c.1415_1416del (p.Ter472CysextTer?)	MMP13	Uncertain significance	criteria provided, single submitter
301979	NM_002427.4(MMP13):c.1080T>C (p.Tyr360=)	MMP13	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
301986	NM_002427.4(MMP13):c.799+7C>T	MMP13	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
MMP13	Definitive	Autosomal recessive	metaphyseal chondrodysplasia, Spahr type	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMP13	Orphanet:1040	Metaphyseal anadysplasia
MMP13	Orphanet:2501	Metaphyseal chondrodysplasia, Spahr type
MMP13	Orphanet:93356	Spondyloepimetaphyseal dysplasia, Missouri type

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
MMP13	HGNC:7159	ENSG00000137745	P45452	Collagenase 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMP13	Collagenase 3	Plays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMP13	Protease	yes	3.4.24.17	Hemopexin-like_dom, Pept_M10_metallopeptidase, Peptidoglycan-bd-like

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
cartilage tissue	1
periodontal ligament	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMP13	62	tissue_specific	marker	periodontal ligament, cartilage tissue, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMP13	2,467

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMP13	P45452	49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
RUNX2 regulates genes involved in cell migration	1	1427.5×	0.008	MMP13
Collagen formation	1	456.8×	0.010	MMP13
Activation of Matrix Metalloproteinases	1	308.6×	0.010	MMP13
Transcriptional regulation by RUNX2	1	253.8×	0.010	MMP13
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.010	MMP13
Collagen degradation	1	175.7×	0.010	MMP13
Degradation of the extracellular matrix	1	117.7×	0.013	MMP13
Extracellular matrix organization	1	63.1×	0.022	MMP13
RNA Polymerase II Transcription	1	22.5×	0.054	MMP13
Gene expression (Transcription)	1	17.8×	0.062	MMP13
Generic Transcription Pathway	1	15.1×	0.066	MMP13

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
growth plate cartilage development	1	2106.5×	0.004	MMP13
response to amyloid-beta	1	991.3×	0.004	MMP13
bone morphogenesis	1	601.9×	0.004	MMP13
endochondral ossification	1	543.6×	0.004	MMP13
collagen catabolic process	1	391.9×	0.004	MMP13
extracellular matrix disassembly	1	366.4×	0.004	MMP13
bone mineralization	1	271.8×	0.005	MMP13
extracellular matrix organization	1	122.1×	0.009	MMP13
proteolysis	1	34.2×	0.029	MMP13

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MMP13	CHLOROXINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMP13	13	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHLOROXINE	4	MMP13
DOXYCYCLINE	4	MMP13
CURCUMIN	3	MMP13
MARIMASTAT	3	MMP13
QUERCETIN	3	MMP13
PRINOMASTAT	3	MMP13
CIPEMASTAT	2	MMP13
LUTEOLIN	2	MMP13
ILOMASTAT	2	MMP13
APRATASTAT	2	MMP13
TANOMASTAT	2	MMP13
BATIMASTAT	2	MMP13
CTS-1027	2	MMP13

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MMP13	452	Binding:435, ADMET:8, Functional:6, Unclassified:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMP13	3.4.24.17, 3.4.24.35, 3.4.24.65, 3.4.24.B4	stromelysin 1, gelatinase B, macrophage elastase,

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MMP13	452

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

13 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.

Compound	Max phase	Cohort target (bioactivity)
CHLOROXINE	4	MMP13
DOXYCYCLINE	4	MMP13
CURCUMIN	3	MMP13
MARIMASTAT	3	MMP13
QUERCETIN	3	MMP13
PRINOMASTAT	3	MMP13
CIPEMASTAT	2	MMP13
LUTEOLIN	2	MMP13
ILOMASTAT	2	MMP13
APRATASTAT	2	MMP13
TANOMASTAT	2	MMP13
BATIMASTAT	2	MMP13
CTS-1027	2	MMP13

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MMP13
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.