Otospondylomegaepiphyseal dysplasia, autosomal dominant

Summary

Otospondylomegaepiphyseal dysplasia, autosomal dominant (MONDO:0008490) is a disease caused by COL11A2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: COL11A2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 137
• Phenotypes (HPO): 12

Clinical features

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0000162	Glossoptosis	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0002758	Osteoarthritis	Frequent (30-79%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000768	Pectus carinatum	Occasional (5-29%)
HP:0005916	Abnormal metacarpal morphology	Occasional (5-29%)
HP:0100777	Exostoses	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	otospondylomegaepiphyseal dysplasia, autosomal dominant
Mondo ID	MONDO:0008490
MeSH	C535776, C537494
OMIM	184840, 277610
Orphanet	166100, 3450
DOID	DOID:0080677, DOID:4258
SNOMED CT	699313003
UMLS	C1848488
MedGen	341234
GARD	0005021
NORD	1533
Is cancer (heuristic)	no

Also known as: COL11A2 Stickler syndrome · heterozygous OSMED · heterozygous otospondylomegaepiphyseal dysplasia · OSMED, Heterozygous · OSMED, heterozygous · OSMEDA · otospondylomegaepiphyseal dysplasia, autosomal dominant · Pierre Robin sequence-fetal chondrodysplasia syndrome · Pierre Robin syndrome with fetal chondrodysplasia · Pierre Robin syndrome with fetal chondrodysplasia Stickler syndrome, Nonocular type · Pierre Robin syndrome with fetal chondrodysplasia Stickler syndrome, Nonocular type, formerly · Pierre Robin syndrome with foetal chondrodysplasia · Pierre Robin syndrome with foetal chondrodysplasia Stickler syndrome, Nonocular type · Pierre Robin syndrome with foetal chondrodysplasia Stickler syndrome, Nonocular type, formerly · Pierre Robin syndrome-fetal chondrodysplasia syndrome · Stickler syndrome caused by mutation in COL11A2 · Stickler syndrome nonocular type · Stickler syndrome, non-ocular type · Stickler syndrome, Nonocular type · Stickler syndrome, type 3 (+6 more)

Data availability: 137 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 › spondyloepiphyseal dysplasia › otospondylomegaepiphyseal dysplasia › otospondylomegaepiphyseal dysplasia, autosomal dominant

Related subtypes (1): otospondylomegaepiphyseal dysplasia, autosomal recessive

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

137 retrieved; paginated sample, class counts are floors:

57 conflicting classifications of pathogenicity, 35 uncertain significance, 15 benign, 10 likely pathogenic, 8 pathogenic, 7 pathogenic/likely pathogenic, 3 likely benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1334054	NM_080680.3(COL11A2):c.2690del (p.Pro897fs)	COL11A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447541	NM_080680.3(COL11A2):c.1135C>T (p.Arg379Ter)	COL11A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17120	NM_080680.3(COL11A2):c.4392+1G>A	COL11A2	Pathogenic	criteria provided, multiple submitters, no conflicts
17122	NM_080680.3(COL11A2):c.2822_2848del (p.Glu941_Pro950delinsAla)	COL11A2	Pathogenic	no assertion criteria provided
17123	NM_080680.3(COL11A2):c.4322G>A (p.Gly1441Glu)	COL11A2	Pathogenic	no assertion criteria provided
17127	NM_080680.3(COL11A2):c.4135C>T (p.Arg1379Ter)	COL11A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17128	NM_080680.3(COL11A2):c.3991C>T (p.Arg1331Ter)	COL11A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2757004	NM_080680.3(COL11A2):c.3329dup (p.Gly1111fs)	COL11A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2904699	NM_080680.3(COL11A2):c.2158C>T (p.Arg720Ter)	COL11A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2913625	NM_080680.3(COL11A2):c.4798C>T (p.Arg1600Ter)	COL11A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3017031	NM_080680.3(COL11A2):c.1297C>T (p.Arg433Ter)	COL11A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423882	NM_080680.3(COL11A2):c.3058C>T (p.Arg1020Ter)	COL11A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694708	NM_080680.3(COL11A2):c.4465G>A (p.Gly1489Ser)	COL11A2	Pathogenic	criteria provided, single submitter
694704	NM_001844.5(COL2A1):c.3714C>A (p.Tyr1238Ter)	COL2A1	Pathogenic	criteria provided, single submitter
694725	NM_001844.5(COL2A1):c.1129G>A (p.Ala377Thr)	COL2A1	Pathogenic	criteria provided, single submitter
2439215	NM_080680.3(COL11A2):c.2843dup (p.Pro950fs)	COL11A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593490	NM_080680.3(COL11A2):c.4081A>T (p.Lys1361Ter)	COL11A2	Likely pathogenic	criteria provided, single submitter
3593492	NM_080680.3(COL11A2):c.3746G>A (p.Gly1249Glu)	COL11A2	Likely pathogenic	criteria provided, single submitter
3593493	NM_080680.3(COL11A2):c.2734_2736+14del	COL11A2	Likely pathogenic	criteria provided, single submitter
3593494	NM_080680.3(COL11A2):c.2589dup (p.Ser864fs)	COL11A2	Likely pathogenic	criteria provided, single submitter
3593495	NM_080680.3(COL11A2):c.2567G>A (p.Gly856Glu)	COL11A2	Likely pathogenic	criteria provided, single submitter
3593497	NM_080680.3(COL11A2):c.2062G>A (p.Gly688Arg)	COL11A2	Likely pathogenic	criteria provided, single submitter
3593499	NM_080680.3(COL11A2):c.129_132dup (p.Asp45delinsProTer)	COL11A2	Likely pathogenic	criteria provided, single submitter
4795106	NM_080680.3(COL11A2):c.1901G>C (p.Gly634Ala)	COL11A2	Likely pathogenic	criteria provided, single submitter
497711	NM_080680.3(COL11A2):c.1719+3dup	COL11A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1129450	NM_080680.3(COL11A2):c.2220G>T (p.Glu740Asp)	COL11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1200125	NM_080680.3(COL11A2):c.973G>A (p.Asp325Asn)	COL11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213287	NM_080680.3(COL11A2):c.1999G>A (p.Gly667Ser)	COL11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1375471	NM_080680.3(COL11A2):c.1399G>A (p.Val467Met)	COL11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1398032	NM_080680.3(COL11A2):c.2179G>A (p.Gly727Arg)	COL11A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 23 · 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
COL11A2	Definitive	Autosomal dominant	otospondylomegaepiphyseal dysplasia	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita

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
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	gencc,clinvar
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1
cartilage tissue	1
corpus epididymis	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL11A2	134	broad	yes	pituitary gland, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491
COL11A2	1,583

Intra-cohort edges

A	B	Sources
COL11A2	COL2A1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL11A2	P13942	50.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
MET activates PTK2 signaling	2	380.7×	7e-05	COL11A2, COL2A1
Collagen chain trimerization	2	259.6×	7e-05	COL11A2, COL2A1
Developmental Lineage of Pancreatic Ductal Cells	2	228.4×	7e-05	COL11A2, COL2A1
Assembly of collagen fibrils and other multimeric structures	2	200.3×	7e-05	COL11A2, COL2A1
Collagen degradation	2	175.7×	7e-05	COL11A2, COL2A1
Collagen biosynthesis and modifying enzymes	2	170.4×	7e-05	COL11A2, COL2A1
Non-integrin membrane-ECM interactions	2	154.3×	8e-05	COL11A2, COL2A1
Fibronectin matrix formation	1	285.5×	0.006	COL2A1
Signaling by PDGF	1	126.9×	0.010	COL2A1
NCAM1 interactions	1	124.1×	0.010	COL2A1
ECM proteoglycans	1	75.1×	0.016	COL2A1
Integrin cell surface interactions	1	67.2×	0.016	COL2A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.023	COL2A1

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
cartilage development	2	251.5×	2e-04	COL11A2, COL2A1
roof of mouth development	2	247.8×	2e-04	COL11A2, COL2A1
collagen fibril organization	2	224.7×	2e-04	COL11A2, COL2A1
skeletal system development	2	125.8×	4e-04	COL11A2, COL2A1
sensory perception of sound	2	100.9×	5e-04	COL11A2, COL2A1
soft palate development	1	1685.2×	0.002	COL11A2
otic vesicle development	1	1404.3×	0.002	COL2A1
anterior head development	1	1404.3×	0.002	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.002	COL2A1
proteoglycan metabolic process	1	936.2×	0.003	COL2A1
notochord development	1	842.6×	0.003	COL2A1
limb bud formation	1	766.0×	0.003	COL2A1
embryonic skeletal joint morphogenesis	1	766.0×	0.003	COL2A1
cartilage condensation	1	383.0×	0.005	COL2A1
tissue homeostasis	1	280.9×	0.005	COL2A1
cellular response to BMP stimulus	1	280.9×	0.005	COL2A1
endochondral ossification	1	271.8×	0.005	COL2A1
extrinsic apoptotic signaling pathway in absence of ligand	1	234.1×	0.006	COL2A1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	205.5×	0.006	COL2A1
heart morphogenesis	1	187.2×	0.007	COL2A1
chondrocyte differentiation	1	150.5×	0.008	COL2A1
inner ear morphogenesis	1	150.5×	0.008	COL2A1
central nervous system development	1	57.7×	0.019	COL2A1
regulation of gene expression	1	41.7×	0.025	COL2A1
visual perception	1	39.8×	0.025	COL2A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL11A2	0	0
COL2A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
COL2A1	2	Binding:2

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL11A2, COL2A1

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)
COL11A2	0	—
COL2A1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.