Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

Summary

Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (MONDO:0100462) is a disease caused by ACAN (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ACAN (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 117

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans
Mondo ID	MONDO:0100462
OMIM	165800
Orphanet	251262
UMLS	C3665488
MedGen	777109
GARD	0004133
Is cancer (heuristic)	no

Also known as: OD · osteochondritis dissecans and short stature · osteochondritis dissecans, short stature, and early-onset osteoarthritis · SSOAOD

Data availability: 117 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › osteonecrosis of genetic origin › short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

Related subtypes (11): Legg-Calve-Perthes disease, Thiemann disease, familial form, Scheuermann disease, Gaucher disease type I, dihydropyrimidine dehydrogenase deficiency, familial avascular necrosis of femoral head, pseudohypoparathyroidism type 1C, hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency, hereditary antithrombin deficiency, osteochondritis dissecans, epiphysiolysis of the hip

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:

32 likely pathogenic, 28 benign, 22 pathogenic, 21 uncertain significance, 8 benign/likely benign, 4 pathogenic/likely pathogenic, 1 uncertain risk allele, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1687107	Single allele		Pathogenic	no assertion criteria provided
1687628	Single allele		Pathogenic	no assertion criteria provided
1691680	Single allele		Pathogenic	no assertion criteria provided
1069109	NM_001369268.1(ACAN):c.1097dup (p.Gly366_Glu367insTer)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
1189835	NM_001369268.1(ACAN):c.492C>A (p.Tyr164Ter)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
1328253	NM_001369268.1(ACAN):c.2023C>T (p.Arg675Ter)	ACAN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328336	NM_001369268.1(ACAN):c.1608C>A (p.Tyr536Ter)	ACAN	Pathogenic	criteria provided, single submitter
1332835	NM_001369268.1(ACAN):c.1605-2A>C	ACAN	Pathogenic	criteria provided, single submitter
1426035	NM_001369268.1(ACAN):c.867del (p.Trp290fs)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
14306	NM_001369268.1(ACAN):c.7363G>A (p.Val2455Met)	ACAN	Pathogenic	no assertion criteria provided
1438177	NM_001369268.1(ACAN):c.1130G>A (p.Trp377Ter)	ACAN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526221	NM_001369268.1(ACAN):c.301C>T (p.Gln101Ter)	ACAN	Pathogenic	criteria provided, single submitter
1685497	NM_001369268.1(ACAN):c.4474del (p.Ser1492fs)	ACAN	Pathogenic	criteria provided, single submitter
1992362	NM_001369268.1(ACAN):c.2002dup (p.Arg668fs)	ACAN	Pathogenic	criteria provided, single submitter
2122084	NM_001369268.1(ACAN):c.1551C>G (p.Tyr517Ter)	ACAN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506423	NM_001369268.1(ACAN):c.6679C>T (p.Gln2227Ter)	ACAN	Pathogenic	no assertion criteria provided
2671894	NM_001369268.1(ACAN):c.1429+1G>C	ACAN	Pathogenic	criteria provided, single submitter
2768773	NM_001369268.1(ACAN):c.706C>T (p.Arg236Ter)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
2819253	NM_001369268.1(ACAN):c.760G>T (p.Glu254Ter)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
3135175	NM_001369268.1(ACAN):c.361C>T (p.Gln121Ter)	ACAN	Pathogenic	criteria provided, single submitter
3237343	NM_001369268.1(ACAN):c.1534C>T (p.Gln512Ter)	ACAN	Pathogenic	no assertion criteria provided
3342274	NM_001369268.1(ACAN):c.2112dup (p.Val705fs)	ACAN	Pathogenic	criteria provided, single submitter
4294352	NM_001369268.1(ACAN):c.7302+1G>A	ACAN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
440746	NM_001369268.1(ACAN):c.7178T>C (p.Leu2393Pro)	ACAN	Pathogenic	no assertion criteria provided
440752	NM_001369268.1(ACAN):c.7204C>T (p.Gln2402Ter)	ACAN	Pathogenic	criteria provided, single submitter
4813607	NM_001369268.1(ACAN):c.1793G>A (p.Cys598Tyr)	ACAN	Pathogenic	criteria provided, single submitter
1068416	NM_001369268.1(ACAN):c.1733-2A>G	ACAN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342158	NM_001369268.1(ACAN):c.293_315del (p.Ser98fs)	ACAN	Likely pathogenic	criteria provided, single submitter
14305	NM_001369268.1(ACAN):c.7255G>A (p.Asp2419Asn)	ACAN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1473730	NM_001369268.1(ACAN):c.1429+1G>T	ACAN	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · 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
ACAN	Definitive	Autosomal dominant	short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACAN	Orphanet:171866	Spondyloepimetaphyseal dysplasia, aggrecan type
ACAN	Orphanet:251262	Familial osteochondritis dissecans
ACAN	Orphanet:435804	Short stature-advanced bone age-early-onset osteoarthritis syndrome
ACAN	Orphanet:93283	Spondyloepiphyseal dysplasia, Kimberley 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
ACAN	HGNC:319	ENSG00000157766	P16112	Aggrecan core protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACAN	Aggrecan core protein	This proteoglycan is a major component of extracellular matrix of cartilagenous tissues.

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
Complement	1	268.0×	0.004

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACAN	Complement	yes		Sushi_SCR_CCP_dom, Link_dom, EGF

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
descending thoracic aorta	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACAN	181	broad	marker	tibia, cartilage tissue, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACAN	2,200

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACAN	P16112	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Defective CHST6 causes MCDC1	1	1427.5×	0.002	ACAN
Defective ST3GAL3 causes MCT12 and EIEE15	1	1427.5×	0.002	ACAN
Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)	1	1427.5×	0.002	ACAN
Keratan sulfate degradation	1	713.8×	0.002	ACAN
Keratan sulfate biosynthesis	1	380.7×	0.004	ACAN
ECM proteoglycans	1	150.3×	0.008	ACAN
Degradation of the extracellular matrix	1	117.7×	0.008	ACAN

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
skeletal system development	1	125.8×	0.017	ACAN
central nervous system development	1	115.4×	0.017	ACAN
cell adhesion	1	37.5×	0.029	ACAN
proteolysis	1	34.2×	0.029	ACAN

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
ACAN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	ACAN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACAN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.