Exostoses, multiple, type 1

Summary

Exostoses, multiple, type 1 (MONDO:0007585) is a disease caused by EXT1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: EXT1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 150

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	exostoses, multiple, type 1
Mondo ID	MONDO:0007585
OMIM	133700
GARD	0002204
Is cancer (heuristic)	no

Also known as: exostoses, multiple caused by mutation in EXT1 · exostoses, multiple, type 1 · EXT · EXT1 exostoses, multiple

Data availability: 150 ClinVar variants · 4 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 remodeling disease › hyperostosis › exostosis › hereditary multiple osteochondromas › exostoses, multiple, type 1

Related subtypes (2): exostoses, multiple, type 2, exostoses, multiple, type III

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

150 retrieved; paginated sample, class counts are floors:

52 pathogenic, 28 uncertain significance, 20 likely pathogenic, 13 conflicting classifications of pathogenicity, 12 benign, 11 pathogenic/likely pathogenic, 9 benign/likely benign, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2580301	GRCh37/hg19 8q24.11-24.13(chr8:118185471-126635744)x1	CCN3	Pathogenic	criteria provided, single submitter
1075642	NM_000127.3(EXT1):c.752del (p.Phe250_Leu251insTer)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1208138	NM_000127.3(EXT1):c.1536+1G>A	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1454747	NM_000127.3(EXT1):c.713del (p.Ser238fs)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457654	NM_000127.3(EXT1):c.747del (p.Phe250_Leu251insTer)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1684648	NM_000127.3(EXT1):c.2055+52_*298del	EXT1	Pathogenic	criteria provided, single submitter
2152051	NM_000127.3(EXT1):c.385G>T (p.Glu129Ter)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
225137	GRCh37/hg19 8q24.11(chr8:118825108-119054752)x3	EXT1	Pathogenic	no assertion criteria provided
2418955	NM_000127.3(EXT1):c.1091G>A (p.Trp364Ter)	EXT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2494	NM_000127.3(EXT1):c.416_419dup (p.Ser141fs)	EXT1	Pathogenic	no assertion criteria provided
2495	NM_000127.3(EXT1):c.1019G>T (p.Arg340Leu)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2498	NM_000127.3(EXT1):c.1016G>A (p.Gly339Asp)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2499	NM_000127.3(EXT1):c.357C>A (p.Tyr119Ter)	EXT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500	NM_000127.3(EXT1):c.1018C>T (p.Arg340Cys)	EXT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501	NM_000127.3(EXT1):c.962+1G>C	EXT1	Pathogenic	criteria provided, single submitter
2502	NM_000127.3(EXT1):c.1664dup (p.Asn555fs)	EXT1	Pathogenic	no assertion criteria provided
2503	NM_000127.3(EXT1):c.962+3_962+6del	EXT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572740	NM_000127.3(EXT1):c.1225C>T (p.Gln409Ter)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2584734	NM_000127.3(EXT1):c.1049_1056+1del	EXT1	Pathogenic	criteria provided, single submitter
2584741	NM_000127.3(EXT1):c.651_665delinsTT (p.Lys218fs)	EXT1	Pathogenic	criteria provided, single submitter
265126	NM_000127.3(EXT1):c.803G>A (p.Gly268Glu)	EXT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265129	NM_000127.3(EXT1):c.1019G>A (p.Arg340His)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
265130	NM_000127.3(EXT1):c.1468del (p.Leu490fs)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
265131	NM_000127.3(EXT1):c.1469del (p.Leu490fs)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
265339	NM_000127.3(EXT1):c.538_539del (p.Leu181fs)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
279804	NM_000127.3(EXT1):c.1468dup (p.Leu490fs)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3069172	NM_000127.3(EXT1):c.1722+1G>C	EXT1	Pathogenic	criteria provided, single submitter
3340271	NM_000127.3(EXT1):c.786C>G (p.Tyr262Ter)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3376150	NM_000127.3(EXT1):c.142_143insCCCGCACC (p.His48fs)	EXT1	Pathogenic	criteria provided, single submitter
3385319	NM_000127.3(EXT1):c.493C>T (p.Gln165Ter)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
EXT1	Definitive	Autosomal dominant	exostoses, multiple, type 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EXT1	Orphanet:321	Multiple osteochondromas
EXT1	Orphanet:502	Trichorhinophalangeal syndrome type 2
EXT1	Orphanet:55880	Chondrosarcoma
EXT2	Orphanet:321	Multiple osteochondromas
EXT2	Orphanet:466926	Seizures-scoliosis-macrocephaly syndrome
EXT2	Orphanet:52022	Potocki-Shaffer 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
EXT1	HGNC:3512	ENSG00000182197	Q16394	Exostosin-1	gencc,clinvar
EXT2	HGNC:3513	ENSG00000151348	Q93063	Exostosin-2	clinvar
CCN3	HGNC:7885	ENSG00000136999	P48745	CCN family member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXT1	Exostosin-1	Glycosyltransferase forming with EXT2 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone.
EXT2	Exostosin-2	Glycosyltransferase forming with EXT1 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone.
CCN3	CCN family member 3	Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EXT1	Enzyme (other)	yes	2.4.1.224	Exostosin, GT64_dom, Nucleotide-diphossugar_trans
EXT2	Enzyme (other)	yes	2.4.1.224	Exostosin, GT64_dom, Nucleotide-diphossugar_trans
CCN3	Other/Unknown	no		IGFBP-like, TSP1_rpt, VWF_dom

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
stromal cell of endometrium	2
descending thoracic aorta	1
saphenous vein	1
cartilage tissue	1
smooth muscle tissue	1
adrenal cortex	1
blood vessel layer	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXT1	285	ubiquitous	marker	stromal cell of endometrium, saphenous vein, descending thoracic aorta
EXT2	269	ubiquitous	marker	stromal cell of endometrium, cartilage tissue, smooth muscle tissue
CCN3	237	ubiquitous	marker	right coronary artery, blood vessel layer, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXT1	1,449
EXT2	1,242
CCN3	768

Intra-cohort edges

A	B	Sources
EXT1	EXT2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EXT1	Q16394	6
EXT2	Q93063	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCN3	P48745	77.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Defective EXT2 causes exostoses 2	2	815.7×	2e-06	EXT1, EXT2
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	2	815.7×	2e-06	EXT1, EXT2
HS-GAG biosynthesis	2	346.1×	8e-06	EXT1, EXT2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fluid transport	2	3744.9×	7e-06	EXT1, EXT2
polysaccharide biosynthetic process	2	1605.0×	2e-05	EXT1, EXT2
heparin proteoglycan biosynthetic process	2	1123.5×	3e-05	EXT1, EXT2
multicellular organismal-level water homeostasis	2	1123.5×	3e-05	EXT1, EXT2
sulfation	2	702.2×	6e-05	EXT1, EXT2
sodium ion homeostasis	2	624.1×	6e-05	EXT1, EXT2
glycosaminoglycan biosynthetic process	2	561.7×	6e-05	EXT1, EXT2
heart contraction	2	510.7×	7e-05	EXT1, EXT2
cell adhesion mediated by integrin	2	449.4×	8e-05	EXT1, CCN3
heparan sulfate proteoglycan biosynthetic process	2	374.5×	9e-05	EXT1, EXT2
hematopoietic stem cell homeostasis	2	374.5×	9e-05	EXT1, CCN3
vasodilation	2	244.2×	2e-04	EXT1, EXT2
chondrocyte differentiation	2	200.6×	3e-04	EXT2, CCN3
ossification	2	151.8×	4e-04	EXT1, EXT2
regulation of blood pressure	2	147.8×	4e-04	EXT1, EXT2
hypersensitivity	1	5617.3×	9e-04	EXT1
heart field specification	1	5617.3×	9e-04	EXT1
lymphocyte adhesion to endothelial cell of high endothelial venule	1	5617.3×	9e-04	EXT1
smoothened signaling pathway involved in lung development	1	5617.3×	9e-04	EXT1
sweat gland development	1	5617.3×	9e-04	EXT1
perichondral bone morphogenesis	1	5617.3×	9e-04	EXT1
smooth muscle cell proliferation	1	2808.7×	0.002	CCN3
stomach development	1	2808.7×	0.002	EXT1
mesenchymal cell differentiation involved in bone development	1	2808.7×	0.002	EXT1
response to leukemia inhibitory factor	1	2808.7×	0.002	EXT1
gene expression	2	53.2×	0.002	EXT1, EXT2
developmental growth involved in morphogenesis	1	1872.4×	0.002	EXT1
response to heparin	1	1872.4×	0.002	EXT1
embryonic skeletal limb joint morphogenesis	1	1404.3×	0.002	EXT1
chondroitin sulfate proteoglycan metabolic process	1	1404.3×	0.002	EXT1

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
EXT1	0	0
EXT2	0	0
CCN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EXT1	2.4.1.224, 2.4.1.225	glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
EXT2	2.4.1.224, 2.4.1.225	glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase

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	2	EXT1, EXT2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CCN3

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)
EXT1	0	—
EXT2	0	—
CCN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.