spondyloepiphyseal dysplasia, Kimberley type

Summary

spondyloepiphyseal dysplasia, Kimberley type (MONDO:0012019) is a disease caused by ACAN (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ACAN (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 73
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		1	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0002655	Spondyloepiphyseal dysplasia	Very frequent (80-99%)
HP:0002758	Osteoarthritis	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0003508	Proportionate short stature	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0010306	Short thorax	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepiphyseal dysplasia, Kimberley type
Mondo ID	MONDO:0012019
MeSH	C564252
OMIM	608361
Orphanet	93283
DOID	DOID:0112282
ICD-11	485470320
SNOMED CT	719203001
UMLS	C1842149
MedGen	330777
GARD	0016814
Is cancer (heuristic)	no

Also known as: SEDK · spondyloepiphyseal dysplasia, Kimberley type

Data availability: 73 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 development disease › osteochondrodysplasia › spondyloepiphyseal dysplasia › spondyloepiphyseal dysplasia, Kimberley type

Related subtypes (43): hip dysplasia, Beukes type, spondyloepiphyseal dysplasia with congenital joint dislocations, Marshall syndrome, metatropic dysplasia, spondyloepiphyseal dysplasia with punctate corneal dystrophy, spondyloepiphyseal dysplasia, MacDermot type, progressive pseudorheumatoid arthropathy of childhood, otospondylomegaepiphyseal dysplasia, Dyggve-Melchior-Clausen disease, dyssegmental dysplasia, Rolland-Desbuquois type, Silverman-Handmaker type dyssegmental dysplasia, Wolcott-Rallison syndrome, Schimke immuno-osseous dysplasia, Richieri Costa-da Silva syndrome, Schwartz-Jampel syndrome, X-linked spondyloepimetaphyseal dysplasia, CODAS syndrome, spondyloepiphyseal dysplasia, Reardon type, brachyolmia-amelogenesis imperfecta syndrome, spondyloepiphyseal dysplasia with coronal craniosynostosis, cataracts, cleft palate, and intellectual disability, anauxetic dysplasia, spondyloepiphyseal dysplasia, Cantu type, Ehlers-Danlos syndrome, spondylocheirodysplastic type, spondylo-megaepiphyseal-metaphyseal dysplasia, brachydactylous dwarfism, Mseleni type, TMEM165-congenital disorder of glycosylation, Steel syndrome, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Roifman syndrome, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, even-plus syndrome, Smith-McCort dysplasia, cono-spondylar dysplasia, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, Stickler syndrome, spondyloepiphyseal dysplasia tarda, spondyloepiphyseal dysplasia, kondo-fu type, spondyloepiphyseal dysplasia, nishimura type, immunoskeletal dysplasia with neurodevelopmental abnormalities, COL2A1-related spondyloepiphyseal dysplasia, MIR140-related spondyloepiphyseal dysplasia, MGP-related spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia, Holling type

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

73 retrieved; paginated sample, class counts are floors:

44 benign, 8 benign/likely benign, 7 likely pathogenic, 7 uncertain significance, 4 pathogenic, 2 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
14304	NM_001369268.1(ACAN):c.3758dup (p.Gly1254fs)	ACAN	Pathogenic	no assertion criteria provided
4082364	NM_001369268.1(ACAN):c.4929del (p.Ser1644fs)	ACAN	Pathogenic	criteria provided, single submitter
1068416	NM_001369268.1(ACAN):c.1733-2A>G	ACAN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3235896	NM_001369268.1(ACAN):c.6993C>A (p.Cys2331Ter)	ACAN	Likely pathogenic	criteria provided, single submitter
3237347	NM_001369268.1(ACAN):c.1748_1764del (p.Ala583fs)	ACAN	Likely pathogenic	no assertion criteria provided
3382910	NM_001369268.1(ACAN):c.2858dup (p.Asp953fs)	ACAN	Likely pathogenic	criteria provided, single submitter
3577865	NM_001369268.1(ACAN):c.2534C>A (p.Ser845Ter)	ACAN	Likely pathogenic	criteria provided, single submitter
3577866	NM_001369268.1(ACAN):c.2587del (p.Ala863fs)	ACAN	Likely pathogenic	criteria provided, single submitter
3764676	NM_001369268.1(ACAN):c.247G>T (p.Glu83Ter)	ACAN	Likely pathogenic	criteria provided, single submitter
1367420	NM_001369268.1(ACAN):c.6945A>T (p.Ile2315=)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1367485	NM_001369268.1(ACAN):c.836G>A (p.Arg279Gln)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679571	NM_001369268.1(ACAN):c.2539C>G (p.Pro847Ala)	ACAN	Uncertain significance	criteria provided, single submitter
3577864	NM_001369268.1(ACAN):c.1624C>T (p.Arg542Trp)	ACAN	Uncertain significance	criteria provided, single submitter
3776755	NM_001369268.1(ACAN):c.1604+48G>C	ACAN	Uncertain significance	criteria provided, single submitter
444004	NM_001369268.1(ACAN):c.1193T>A (p.Ile398Asn)	ACAN	Uncertain significance	criteria provided, single submitter
975931	NM_001369268.1(ACAN):c.262G>A (p.Val88Met)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1174760	NM_001369268.1(ACAN):c.2815T>A (p.Ser939Thr)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1174779	NM_001369268.1(ACAN):c.4207A>G (p.Thr1403Ala)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1174934	NM_001369268.1(ACAN):c.7613A>G (p.Gln2538Arg)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1181962	NM_001369268.1(ACAN):c.2289C>T (p.Pro763=)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1188847	NM_001369268.1(ACAN):c.758-37del	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1188848	NM_001369268.1(ACAN):c.1430-40G>A	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1188849	NM_001369268.1(ACAN):c.1623C>A (p.Pro541=)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1188850	NM_001369268.1(ACAN):c.7631-7G>A	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1188885	NM_001369268.1(ACAN):c.2514G>A (p.Ser838=)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1188886	NM_001369268.1(ACAN):c.2789G>T (p.Ser930Ile)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1188887	NM_001369268.1(ACAN):c.3009C>T (p.Thr1003=)	ACAN	Benign	criteria provided, multiple submitters, no conflicts

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	spondyloepiphyseal dysplasia, Kimberley type	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.