Exostosis

Summary

Exostosis (MONDO:0002181) is a disease with 2 cohort genes (34 GWAS associations across 14 studies) and 1 clinical trial.

At a glance

• Cohort genes: 2
• GWAS associations: 34
• ClinVar variants: 2
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	exostosis
Mondo ID	MONDO:0002181
DOID	DOID:203
NCIT	C3029
SNOMED CT	235231000119100, 416189003
UMLS	C1442903
MedGen	257035
Is cancer (heuristic)	no

Also known as: bone osteophyte · exostosis · orbital exostosis · swimmer’s exostosis

Data availability: 2 ClinVar variants · 34 GWAS associations (14 studies).

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › hyperostosis › exostosis

Related subtypes (8): bone Paget disease, diffuse idiopathic skeletal hyperostosis, Caffey disease, autosomal dominant osteosclerosis, Worth type, craniodiaphyseal dysplasia, hyperostosis corticalis generalisata, X-linked calvarial hyperostosis, sclerosteosis

Subtypes (3): heel spur, hereditary multiple osteochondromas, Heberden’s node

Genetics & variants

GWAS landscape

34 GWAS associations across 14 studies. Top hits map to 26 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs369611135	3e-15	PCDH9	T	3.12
rs182658227	4e-15	SDK1	A	3.73
rs181552316	3e-14	MITA1 - RPL3P9	G	4.05
rs190073601	1e-13	DENND1B	A	3.96
rs193167778	2e-13	PLB1	C	3.23
rs143106204	2e-13	LINC02997	C	3.61
rs577272962	3e-13	PWRN1	A	3.65
rs140162870	4e-13	NXPH1 - GAPDHP68	C	4.32
rs182756278	6e-13	PRKN	C	4.03
rs139814879	1e-12	LINC01301	T	4.71
rs187052602	2e-12	RNU7-152P - MIR1202	G	2.47
rs146418869	3e-12	AOX2P	A	2.23
rs374462308	3e-12	LINC00540 - FTH1P7	G	4.2
rs556962187	4e-12	KCTD8	G	3.55
rs149729817	4e-12	LINC02873	G	4.32
rs575997043	5e-12	MFF	C	4.88
rs190360312	5e-12	RPSAP37 - LINC02039	G	3.93
rs539018113	5e-12	TPPP2, NDRG2	G	3.37
rs181133730	5e-12	RGS2-AS1	G	3.04
rs139575989	8e-12	LINC02819	G	3.16
rs145505700	9e-12	DDC	A	2.87
rs142291828	9e-12	GSTT4 - CABIN1	C	3.95
rs140861916	1e-11	LINC03019	C	3.3
rs142690927	2e-11	OR2T2 - OR2T3	C	2.29
rs111829969	2e-11	CRYBG1	C	4.83
rs559322533	2e-11	ZFPM2	A	3
rs572272840	2e-11	NETO1	G	2.98
rs181483238	3e-11	LRRTM4 - RPL38P2	G	2.95
rs142726098	3e-11	ELOVL5	T	3.37
rs542887566	4e-11	CAPRIN2, LINC00941	C	3.84

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90478943	Verma A	2024	11,194	421,111	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90080464	Backman JD	2021	3,804	384,122	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90084450	Backman JD	2021	3,804	384,122	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90478942	Verma A	2024	3,221	113,144	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481000	Verma A	2024	3,221	113,144	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90478941	Verma A	2024	1,346	56,156	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90080463	Backman JD	2021	1,044	386,886	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90084449	Backman JD	2021	1,044	386,886	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90080462	Backman JD	2021	874	387,056	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90084448	Backman JD	2021	874	387,056	Exome sequencing and analysis of 454,787 UK Biobank participants.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	32

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	33
unknown	0

Functional consequences

Consequence	Count
intron_variant	25
intergenic_variant	5
non_coding_transcript_exon_variant	2
5_prime_UTR_variant	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs369611135	13	66939612	T>C	0.001	intron_variant	PCDH9	3e-15	Tier 4: intronic/intergenic
rs182658227	7	4046527	A>G	0	intron_variant	SDK1	4e-15	Tier 4: intronic/intergenic
rs181552316	8	79225184	G>A	0.001	intergenic_variant	MITA1 - RPL3P9	3e-14	Tier 4: intronic/intergenic
rs190073601	1	197631281	A>C	0.001	intron_variant	DENND1B	1e-13	Tier 4: intronic/intergenic
rs193167778	2	28616781	C>A	0.001	intron_variant	PLB1	2e-13	Tier 4: intronic/intergenic
rs143106204	5	67752462	C>T	0.001	intron_variant	LINC02997	2e-13	Tier 4: intronic/intergenic
rs577272962	15	24553907	A>G	0.001	intron_variant	PWRN1	3e-13	Tier 4: intronic/intergenic
rs140162870	7	9242187	C>A,G,T	0	intergenic_variant	NXPH1 - GAPDHP68	4e-13	Tier 4: intronic/intergenic
rs182756278	6	161693033	C>T	0	intron_variant	PRKN	6e-13	Tier 4: intronic/intergenic
rs139814879	8	60416191	T>A,C	0.001	intron_variant	LINC01301	1e-12	Tier 4: intronic/intergenic
rs187052602	6	155928389	G>A	0.001	intron_variant	RNU7-152P - MIR1202	2e-12	Tier 4: intronic/intergenic
rs146418869	2	200764601	A>T	0.001	non_coding_transcript_exon_variant	AOX2P	3e-12	Tier 4: intronic/intergenic
rs374462308	13	22575527	G>A	0	intergenic_variant	LINC00540 - FTH1P7	3e-12	Tier 4: intronic/intergenic
rs556962187	4	44441887	G>A	0	intron_variant	KCTD8	4e-12	Tier 4: intronic/intergenic
rs149729817	11	130649377	G>A	0	intron_variant	LINC02873	4e-12	Tier 4: intronic/intergenic
rs575997043	2	227328580	C>T	0	intron_variant	MFF	5e-12	Tier 4: intronic/intergenic
rs190360312	5	126082610	G>A,C	0	intron_variant	RPSAP37 - LINC02039	5e-12	Tier 4: intronic/intergenic
rs539018113	14	21025606	G>A,T	0	5_prime_UTR_variant	TPPP2, NDRG2	5e-12	Tier 2: splice/UTR
rs181133730	1	192508604	G>A,T	0.001	intron_variant	RGS2-AS1	5e-12	Tier 4: intronic/intergenic
rs139575989	1	159487428	G>A	0.001	intron_variant	LINC02819	8e-12	Tier 4: intronic/intergenic
rs145505700	7	50529800	A>G	0.001	intron_variant	DDC	9e-12	Tier 4: intronic/intergenic
rs142291828	22	24008781	C>G,T	0.001	non_coding_transcript_exon_variant	GSTT4 - CABIN1	9e-12	Tier 4: intronic/intergenic
rs140861916	8	12774852	C>T	0	intron_variant	LINC03019	1e-11	Tier 4: intronic/intergenic
rs142690927	1	248469393	C>T	0.004	intergenic_variant	OR2T2 - OR2T3	2e-11	Tier 4: intronic/intergenic
rs111829969	6	106415893	C>T	0.001	intron_variant	CRYBG1	2e-11	Tier 4: intronic/intergenic
rs559322533	8	105347887	A>T	0.001	intron_variant	ZFPM2	2e-11	Tier 4: intronic/intergenic
rs572272840	18	72847139	G>T	0.001	intron_variant	NETO1	2e-11	Tier 4: intronic/intergenic
rs181483238	2	77705532	G>A	0	intron_variant	LRRTM4 - RPL38P2	3e-11	Tier 4: intronic/intergenic
rs142726098	6	53286599	T>C	0.001	intron_variant	ELOVL5	3e-11	Tier 4: intronic/intergenic
rs542887566	12	30805025	C>A,T	0	intron_variant	CAPRIN2, LINC00941	4e-11	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
863192	NM_000127.3(EXT1):c.1722+1G>T	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
523482	NM_001374353.1(GLI2):c.2593A>T (p.Thr865Ser)	GLI2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms

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
EXT1	HGNC:3512	ENSG00000182197	Q16394	Exostosin-1	clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	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.
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EXT1	Enzyme (other)	yes	2.4.1.224	Exostosin, GT64_dom, Nucleotide-diphossugar_trans
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

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
descending thoracic aorta	1
saphenous vein	1
stromal cell of endometrium	1
germinal epithelium of ovary	1
tibia	1
ventricular zone	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
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI2	3,112
EXT1	1,449

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EXT1	Q16394	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
RUNX2 regulates chondrocyte maturation	1	1142.0×	0.005	GLI2
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	815.7×	0.005	GLI2
Defective EXT2 causes exostoses 2	1	407.9×	0.005	EXT1
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	1	407.9×	0.005	EXT1
HS-GAG biosynthesis	1	173.0×	0.009	EXT1
Degradation of GLI2 by the proteasome	1	112.0×	0.012	GLI2
Hedgehog ‘off’ state	1	89.2×	0.013	GLI2
Hedgehog ‘on’ state	1	79.3×	0.013	GLI2

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
hair follicle morphogenesis	2	495.6×	5e-04	EXT1, GLI2
cellular response to virus	2	200.6×	0.001	EXT1, GLI2
hypersensitivity	1	8426.0×	0.002	EXT1
heart field specification	1	8426.0×	0.002	EXT1
lymphocyte adhesion to endothelial cell of high endothelial venule	1	8426.0×	0.002	EXT1
smoothened signaling pathway involved in lung development	1	8426.0×	0.002	EXT1
sweat gland development	1	8426.0×	0.002	EXT1
perichondral bone morphogenesis	1	8426.0×	0.002	EXT1
axon guidance	2	90.6×	0.002	EXT1, GLI2
stomach development	1	4213.0×	0.002	EXT1
mesenchymal cell differentiation involved in bone development	1	4213.0×	0.002	EXT1
response to leukemia inhibitory factor	1	4213.0×	0.002	EXT1
ventral midline development	1	2808.7×	0.002	GLI2
floor plate formation	1	2808.7×	0.002	GLI2
spinal cord ventral commissure morphogenesis	1	2808.7×	0.002	GLI2
fluid transport	1	2808.7×	0.002	EXT1
developmental growth involved in morphogenesis	1	2808.7×	0.002	EXT1
response to heparin	1	2808.7×	0.002	EXT1
hindgut morphogenesis	1	2106.5×	0.002	GLI2
tube development	1	2106.5×	0.002	GLI2
embryonic skeletal limb joint morphogenesis	1	2106.5×	0.002	EXT1
chondroitin sulfate proteoglycan metabolic process	1	2106.5×	0.002	EXT1
bone trabecula morphogenesis	1	2106.5×	0.002	EXT1
chondrocyte hypertrophy	1	1685.2×	0.003	EXT1
hematopoietic stem cell migration to bone marrow	1	1685.2×	0.003	EXT1
tight junction organization	1	1685.2×	0.003	EXT1
chondrocyte differentiation involved in endochondral bone morphogenesis	1	1404.3×	0.003	EXT1
cerebellar cortex morphogenesis	1	1404.3×	0.003	GLI2
fear response	1	1404.3×	0.003	EXT1
polysaccharide biosynthetic process	1	1203.7×	0.003	EXT1

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
EXT1	0	0
GLI2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GLI2	6	Binding:6

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

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	1	EXT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GLI2

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)
EXT1	0	—
GLI2	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06266208	Not specified	COMPLETED	Utility of High-resolution Ultrasound to Evaluate Dorsal Osteophyte