Spondyloepiphyseal dysplasia congenita

Summary

Spondyloepiphyseal dysplasia congenita (MONDO:0008471) is a disease caused by COL2A1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: COL2A1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 105
• Phenotypes (HPO): 42
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002938	Lumbar hyperlordosis	Very frequent (80-99%)
HP:0003521	Disproportionate short-trunk short stature	Very frequent (80-99%)
HP:0010575	Dysplasia of the femoral head	Very frequent (80-99%)
HP:0045060	Aplasia/hypoplasia involving bones of the extremities	Very frequent (80-99%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000926	Platyspondyly	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0003180	Flat acetabular roof	Frequent (30-79%)
HP:0009824	Upper limb undergrowth	Frequent (30-79%)
HP:0012368	Flat face	Frequent (30-79%)
HP:0030838	Hip pain	Frequent (30-79%)
HP:0040194	Increased head circumference	Frequent (30-79%)
HP:0100569	Abnormally ossified vertebrae	Frequent (30-79%)
HP:0000162	Glossoptosis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001552	Barrel-shaped chest	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0002176	Spinal cord compression	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002795	Abnormal respiratory system physiology	Occasional (5-29%)
HP:0002996	Limited elbow movement	Occasional (5-29%)
HP:0003026	Short long bone	Occasional (5-29%)
HP:0003097	Short femur	Occasional (5-29%)
HP:0003306	Spinal rigidity	Occasional (5-29%)
HP:0003418	Back pain	Occasional (5-29%)
HP:0004349	Reduced bone mineral density	Occasional (5-29%)
HP:0008462	Cervical instability	Occasional (5-29%)
HP:0008755	Laryngotracheomalacia	Occasional (5-29%)
HP:0010585	Small epiphyses	Occasional (5-29%)
HP:0030839	Knee pain	Occasional (5-29%)
HP:0100864	Short femoral neck	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepiphyseal dysplasia congenita
Mondo ID	MONDO:0008471
MeSH	C535788
OMIM	183900
Orphanet	94068
DOID	DOID:14789
SNOMED CT	278713008
UMLS	C2745959
MedGen	412530
GARD	0004987
MedDRA	10062920
NORD	1733
Is cancer (heuristic)	no

Also known as: congenital spondyloepiphyseal dysplasia · SED congenita · SEDC · spondyloepiphyseal dysplasia congenita · Spondyloepiphyseal Dysplasia, Congenital · spondyloepiphyseal dysplasia, congenital type · Spranger-Wiedemann disease

Data availability: 105 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › type 2 collagenopathy › spondyloepiphyseal dysplasia congenita

Related subtypes (13): Stickler syndrome type 1, multiple epiphyseal dysplasia, Beighton type, platyspondylic dysplasia, Torrance type, Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, ‘corner fracture’ type, achondrogenesis type II, spondyloperipheral dysplasia, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloepiphyseal dysplasia, Stanescu type, hypochondrogenesis, dysplasia of the proximal femoral epiphyses

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

105 retrieved; paginated sample, class counts are floors:

28 pathogenic, 21 conflicting classifications of pathogenicity, 17 likely pathogenic, 14 pathogenic/likely pathogenic, 11 uncertain significance, 9 benign/likely benign, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067522	NM_001844.5(COL2A1):c.3436G>A (p.Gly1146Ser)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074468	NM_001844.5(COL2A1):c.1A>G (p.Met1Val)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1224342	NM_001844.5(COL2A1):c.3121G>A (p.Gly1041Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1326876	NM_001844.5(COL2A1):c.1780G>A (p.Gly594Arg)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326877	NM_001844.5(COL2A1):c.2095G>T (p.Gly699Cys)	COL2A1	Pathogenic	criteria provided, single submitter
1326878	NM_001844.5(COL2A1):c.2671G>A (p.Gly891Ser)	COL2A1	Pathogenic	criteria provided, single submitter
1326879	NM_001844.5(COL2A1):c.3346G>T (p.Gly1116Cys)	COL2A1	Pathogenic	criteria provided, single submitter
1326880	NM_001844.5(COL2A1):c.3463G>C (p.Gly1155Arg)	COL2A1	Pathogenic	criteria provided, single submitter
1326882	NM_001844.5(COL2A1):c.3589G>C (p.Gly1197Arg)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1326892	NM_001844.5(COL2A1):c.980G>T (p.Gly327Val)	COL2A1	Pathogenic	criteria provided, single submitter
1326893	NM_001844.5(COL2A1):c.1069G>A (p.Gly357Ser)	COL2A1	Pathogenic	criteria provided, single submitter
1326895	NM_001844.5(COL2A1):c.1195G>A (p.Gly399Arg)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1343392	NM_001844.5(COL2A1):c.2780G>T (p.Gly927Val)	COL2A1	Pathogenic	no assertion criteria provided
1455692	NM_001844.5(COL2A1):c.2858del (p.Pro953fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17351	NM_001844.5(COL2A1):c.3489+163_3597+2del	COL2A1	Pathogenic	no assertion criteria provided
17361	NM_001844.5(COL2A1):c.3589G>A (p.Gly1197Ser)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17366	NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17381	NM_001844.5(COL2A1):c.3517G>C (p.Gly1173Arg)	COL2A1	Pathogenic	no assertion criteria provided
17383	NM_001844.5(COL2A1):c.1693C>T (p.Arg565Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17393	NM_001844.5(COL2A1):c.3508G>A (p.Gly1170Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17395	NM_001844.5(COL2A1):c.1957C>T (p.Arg653Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
195148	NM_001844.5(COL2A1):c.258C>A (p.Cys86Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
195742	NM_001844.5(COL2A1):c.1510G>A (p.Gly504Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
197564	NM_001844.5(COL2A1):c.3275G>A (p.Gly1092Asp)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208169	NM_001844.5(COL2A1):c.3301G>A (p.Gly1101Arg)	COL2A1	Pathogenic	criteria provided, single submitter
2429070	NM_001844.5(COL2A1):c.610-2A>G	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265429	NM_001844.5(COL2A1):c.2833G>A (p.Gly945Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
283534	NM_001844.5(COL2A1):c.3574C>T (p.Arg1192Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
284348	NM_001844.5(COL2A1):c.2600G>T (p.Gly867Val)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2859637	NM_001844.5(COL2A1):c.3085G>T (p.Gly1029Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 46 · Orphanet: 18 · 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
COL2A1	Definitive	Autosomal dominant	spondyloepiphyseal dysplasia with metatarsal shortening	46

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	gencc,clinvar
BNIP1	HGNC:1082	ENSG00000113734	Q12981	Vesicle transport protein SEC20	clinvar
CLASP1	HGNC:17088	ENSG00000074054	Q7Z460	CLIP-associating protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
BNIP1	Vesicle transport protein SEC20	As part of a SNARE complex may be involved in endoplasmic reticulum membranes fusion and be required for the maintenance of endoplasmic reticulum organization.
CLASP1	CLIP-associating protein 1	Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
BNIP1	Other/Unknown	no		Sec20, Sec20_C
CLASP1	Other/Unknown	no		ARM-like, ARM-type_fold, HEAT_type_2

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
cartilage tissue	1
corpus epididymis	1
tibia	1
diaphragm	1
oocyte	1
secondary oocyte	1
calcaneal tendon	1
cortical plate	1
dorsal motor nucleus of vagus nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
BNIP1	226	ubiquitous	marker	secondary oocyte, oocyte, diaphragm
CLASP1	286	ubiquitous	marker	cortical plate, calcaneal tendon, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491
CLASP1	1,686
BNIP1	1,672

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11
CLASP1	Q7Z460	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BNIP1	Q12981	80.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Role of ABL in ROBO-SLIT signaling	1	423.0×	0.037	CLASP1
Fibronectin matrix formation	1	190.3×	0.037	COL2A1
MET activates PTK2 signaling	1	126.9×	0.037	COL2A1
Collagen chain trimerization	1	86.5×	0.037	COL2A1
Signaling by PDGF	1	84.6×	0.037	COL2A1
NCAM1 interactions	1	82.8×	0.037	COL2A1
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.037	COL2A1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.037	COL2A1
Collagen degradation	1	58.6×	0.037	COL2A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.037	COL2A1
Loss of Nlp from mitotic centrosomes	1	52.9×	0.037	CLASP1
Loss of proteins required for interphase microtubule organization from the centrosome	1	52.9×	0.037	CLASP1
Non-integrin membrane-ECM interactions	1	51.4×	0.037	COL2A1
AURKA Activation by TPX2	1	50.8×	0.037	CLASP1
ECM proteoglycans	1	50.1×	0.037	COL2A1
Recruitment of mitotic centrosome proteins and complexes	1	45.3×	0.037	CLASP1
Integrin cell surface interactions	1	44.8×	0.037	COL2A1
Golgi-to-ER retrograde transport	1	44.3×	0.037	BNIP1
Regulation of PLK1 Activity at G2/M Transition	1	42.3×	0.037	CLASP1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	38.8×	0.037	CLASP1
Recruitment of NuMA to mitotic centrosomes	1	38.8×	0.037	CLASP1
Anchoring of the basal body to the plasma membrane	1	37.7×	0.037	CLASP1
COPI-dependent Golgi-to-ER retrograde traffic	1	37.0×	0.037	BNIP1
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.038	BNIP1
EML4 and NUDC in mitotic spindle formation	1	30.9×	0.041	CLASP1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	29.1×	0.041	COL2A1
Resolution of Sister Chromatid Cohesion	1	28.8×	0.041	CLASP1
RHO GTPases Activate Formins	1	25.9×	0.044	CLASP1
Mitotic Prometaphase	1	23.1×	0.047	CLASP1
Separation of Sister Chromatids	1	20.2×	0.052	CLASP1

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
apoptotic process in response to mitochondrial fragmentation	1	5617.3×	0.008	BNIP1
negative regulation of microtubule polymerization or depolymerization	1	1872.4×	0.008	CLASP1
endoplasmic reticulum membrane fusion	1	1123.5×	0.008	BNIP1
establishment of mitotic spindle localization	1	936.2×	0.008	CLASP1
otic vesicle development	1	936.2×	0.008	COL2A1
anterior head development	1	936.2×	0.008	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	802.5×	0.008	COL2A1
negative regulation of wound healing, spreading of epidermal cells	1	802.5×	0.008	CLASP1
establishment of spindle orientation	1	702.2×	0.008	CLASP1
response to oxygen-glucose deprivation	1	702.2×	0.008	BNIP1
proteoglycan metabolic process	1	624.1×	0.008	COL2A1
obsolete vesicle targeting	1	561.7×	0.008	CLASP1
notochord development	1	561.7×	0.008	COL2A1
limb bud formation	1	510.7×	0.008	COL2A1
embryonic skeletal joint morphogenesis	1	510.7×	0.008	COL2A1
microtubule organizing center organization	1	468.1×	0.008	CLASP1
astral microtubule organization	1	432.1×	0.008	CLASP1
microtubule anchoring	1	432.1×	0.008	CLASP1
positive regulation of extracellular matrix disassembly	1	401.2×	0.008	CLASP1
exit from mitosis	1	351.1×	0.008	CLASP1
cartilage condensation	1	255.3×	0.010	COL2A1
execution phase of apoptosis	1	255.3×	0.010	BNIP1
positive regulation of microtubule polymerization	1	224.7×	0.011	CLASP1
microtubule nucleation	1	208.1×	0.011	CLASP1
positive regulation of exocytosis	1	200.6×	0.011	CLASP1
regulation of focal adhesion assembly	1	200.6×	0.011	CLASP1
negative regulation of stress fiber assembly	1	193.7×	0.011	CLASP1
tissue homeostasis	1	187.2×	0.011	COL2A1
cellular response to BMP stimulus	1	187.2×	0.011	COL2A1
endochondral ossification	1	181.2×	0.011	COL2A1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL2A1	0	0
BNIP1	0	0
CLASP1	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
CLASP1	10	Binding:10
COL2A1	2	Binding:2

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	COL2A1, BNIP1, CLASP1

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)
COL2A1	2	—
BNIP1	0	—
CLASP1	10	—

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
NCT05408715	Not specified	RECRUITING	A Natural History Study in Children With a Type II Collagen Disorder With Short Stature