Spondylometaphyseal dysplasia

Summary

Spondylometaphyseal dysplasia (MONDO:0016763) is a disease (an umbrella term covering 19 Mondo subtypes) with 4 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Umbrella term: 19 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 19

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

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylometaphyseal dysplasia
Mondo ID	MONDO:0016763
OMIM	184255
Orphanet	254
DOID	DOID:0112295
ICD-11	181781948
UMLS	C4759767
MedGen	1674850
GARD	0018685
Is cancer (heuristic)	no

Also known as: spondylometaphyseal dysplasia

Data availability: 19 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 19 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › spondylometaphyseal dysplasia

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, tricho-dento-osseous syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, SHOX-related short stature, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, osteofibrous dysplasia, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, omodysplasia, Bruck syndrome, osteopetrosis, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, craniotubular dysplasia, Ikegawa type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

Subtypes (19): Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Kozlowski type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, ‘corner fracture’ type, spondylometaphyseal dysplasia, Sedaghatian type, spondylometaphyseal dysplasia, Golden type, axial spondylometaphyseal dysplasia, spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome, Spondyloenchondrodysplasia with immune dysregulation, spondylometaphyseal dysplasia-cone-rod dystrophy syndrome, spondylometaphyseal dysplasia, A4 type, spondylometaphyseal dysplasia, East African type, autosomal recessive spondylometaphyseal dysplasia, Megarbane type, spondylometaphyseal dysplasia, Czarny-Ratajczak type, regressive spondylometaphyseal dysplasia, spondylometaphyseal dysplasia, pagnamenta type, odontochondrodysplasia, SBDS-related severe neonatal spondylometaphyseal dysplasia

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

19 retrieved; paginated sample, class counts are floors:

6 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 pathogenic, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
17366	NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)	COL2A1	Pathogenic/Likely 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
424644	NM_212482.4(FN1):c.367T>C (p.Cys123Arg)	FN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424645	NM_212482.4(FN1):c.675C>G (p.Cys225Trp)	FN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549707	NM_212482.4(FN1):c.638G>A (p.Cys213Tyr)	FN1	Pathogenic	criteria provided, single submitter
421465	NM_212482.4(FN1):c.693C>G (p.Cys231Trp)	FN1	Likely pathogenic	criteria provided, single submitter
424643	NM_212482.4(FN1):c.260G>T (p.Cys87Phe)	FN1	Likely pathogenic	criteria provided, single submitter
424646	NM_212482.4(FN1):c.718T>G (p.Tyr240Asp)	FN1	Likely pathogenic	criteria provided, single submitter
424647	NM_212482.4(FN1):c.778T>G (p.Cys260Gly)	FN1	Likely pathogenic	criteria provided, single submitter
549708	NM_212482.4(FN1):c.368G>A (p.Cys123Tyr)	FN1	Likely pathogenic	no assertion criteria provided
549709	NM_212482.4(FN1):c.506G>A (p.Cys169Tyr)	FN1	Likely pathogenic	no assertion criteria provided
308931	NM_001844.5(COL2A1):c.803C>T (p.Pro268Leu)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3718584	NM_001844.5(COL2A1):c.3809G>A (p.Arg1270His)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
845468	NM_001844.5(COL2A1):c.1694G>A (p.Arg565His)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638069	NM_013432.5(TONSL):c.1673G>A (p.Arg558Gln)	TONSL-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547841	NM_001844.5(COL2A1):c.2618G>T (p.Gly873Val)	COL2A1	Uncertain significance	criteria provided, single submitter
424648	NM_212482.4(FN1):c.2422ACA[1] (p.Thr809del)	FN1	Uncertain significance	criteria provided, single submitter
450072	NM_212482.4(FN1):c.773G>A (p.Cys258Tyr)	FN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 21 · 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
PLCB3	Limited	Unknown	spondylometaphyseal dysplasia with corneal dystrophy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLCB3	Orphanet:589435	Spondylometaphyseal dysplasia-corneal dystrophy syndrome
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
FN1	Orphanet:84090	Fibronectin glomerulopathy
FN1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLCB3	HGNC:9056	ENSG00000149782	Q01970	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3	gencc
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	clinvar
FN1	HGNC:3778	ENSG00000115414	P02751	Fibronectin	clinvar
TONSL-AS1	HGNC:51556	ENSG00000232600		TONSL antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLCB3	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3	Catalyzes the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
FN1	Fibronectin	Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Antibody/Immunoglobulin	1	7.3×	0.390
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLCB3	Enzyme (other)	yes	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
FN1	Antibody/Immunoglobulin	yes		Fibronectin_type1, FN_type2_dom, FN3_dom
TONSL-AS1	Other/Unknown	no

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
mucosa of transverse colon	1
small intestine Peyer’s patch	1
cartilage tissue	1
corpus epididymis	1
tibia	1
decidua	1
right coronary artery	1
synovial joint	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLCB3	218	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, small intestine Peyer’s patch
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
FN1	292	ubiquitous	marker	synovial joint, right coronary artery, decidua
TONSL-AS1	124		yes	male germ line stem cell (sensu Vertebrata) in testis, apex of heart, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FN1	8,860
COL2A1	2,491
PLCB3	1,657
TONSL-AS1	0

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FN1	P02751	65
PLCB3	Q01970	13
COL2A1	P02458	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 4 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
Fibronectin matrix formation	2	380.7×	4e-04	COL2A1, FN1
MET activates PTK2 signaling	2	253.8×	4e-04	COL2A1, FN1
Developmental Lineage of Pancreatic Ductal Cells	2	152.3×	8e-04	COL2A1, FN1
Non-integrin membrane-ECM interactions	2	102.9×	0.001	COL2A1, FN1
ECM proteoglycans	2	100.2×	0.001	COL2A1, FN1
Integrin cell surface interactions	2	89.6×	0.001	COL2A1, FN1
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	475.8×	0.013	PLCB3
Acetylcholine regulates insulin secretion	1	380.7×	0.014	PLCB3
ALK mutants bind TKIs	1	317.2×	0.015	FN1
p130Cas linkage to MAPK signaling for integrins	1	253.8×	0.017	FN1
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	237.9×	0.017	FN1
G beta:gamma signalling through PLC beta	1	190.3×	0.018	PLCB3
Presynaptic function of Kainate receptors	1	181.3×	0.018	PLCB3
Attachment of bacteria to epithelial cells	1	165.5×	0.018	FN1
Synthesis of IP3 and IP4 in the cytosol	1	141.0×	0.018	PLCB3
Syndecan interactions	1	141.0×	0.018	FN1
Integrin signaling	1	141.0×	0.018	FN1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.018	FN1
Signaling by high-kinase activity BRAF mutants	1	105.7×	0.018	FN1
Molecules associated with elastic fibres	1	102.9×	0.018	FN1
MAP2K and MAPK activation	1	95.2×	0.018	FN1
Signaling by RAF1 mutants	1	92.8×	0.018	FN1
PLC beta mediated events	1	88.5×	0.018	PLCB3
Collagen chain trimerization	1	86.5×	0.018	COL2A1
Signaling by PDGF	1	84.6×	0.018	COL2A1
Signaling by moderate kinase activity BRAF mutants	1	84.6×	0.018	FN1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	84.6×	0.018	FN1
Signaling downstream of RAS mutants	1	84.6×	0.018	FN1
NCAM1 interactions	1	82.8×	0.018	COL2A1
GPER1 signaling	1	82.8×	0.018	FN1

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
negative regulation of monocyte activation	1	1872.4×	0.008	FN1
calcium-independent cell-matrix adhesion	1	1404.3×	0.008	FN1
positive regulation of substrate-dependent cell migration, cell attachment to substrate	1	1404.3×	0.008	FN1
negative regulation of transforming growth factor beta production	1	1123.5×	0.008	FN1
cell-substrate junction assembly	1	936.2×	0.008	FN1
phospholipase C-activating serotonin receptor signaling pathway	1	936.2×	0.008	PLCB3
biological process involved in interaction with symbiont	1	936.2×	0.008	FN1
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
proteoglycan metabolic process	1	624.1×	0.008	COL2A1
neural crest cell migration involved in autonomic nervous system development	1	624.1×	0.008	FN1
notochord development	1	561.7×	0.008	COL2A1
blood coagulation, fibrin clot formation	1	561.7×	0.008	FN1
limb bud formation	1	510.7×	0.008	COL2A1
embryonic skeletal joint morphogenesis	1	510.7×	0.008	COL2A1
integrin activation	1	468.1×	0.008	FN1
regulation of protein phosphorylation	1	374.5×	0.010	FN1
regulation of systemic arterial blood pressure	1	351.1×	0.010	PLCB3
enteric nervous system development	1	330.4×	0.010	FN1
phosphatidylinositol metabolic process	1	295.6×	0.010	PLCB3
cartilage condensation	1	255.3×	0.012	COL2A1
phosphatidylinositol-mediated signaling	1	234.1×	0.012	PLCB3
response to muscle activity	1	193.7×	0.013	FN1
regulation of ERK1 and ERK2 cascade	1	193.7×	0.013	FN1
tissue homeostasis	1	187.2×	0.013	COL2A1
cellular response to BMP stimulus	1	187.2×	0.013	COL2A1
endochondral ossification	1	181.2×	0.013	COL2A1
positive regulation of axon extension	1	170.2×	0.013	FN1
endodermal cell differentiation	1	165.2×	0.013	FN1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLCB3	0	0
COL2A1	0	0
FN1	0	0
TONSL-AS1	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
PLCB3	2	Binding:2
COL2A1	2	Binding:2
FN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCB3	3.1.4.11	phosphoinositide phospholipase C

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	2	PLCB3, FN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL2A1, TONSL-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLCB3	2	—
COL2A1	2	—
FN1	1	—
TONSL-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.