spondylometaphyseal dysplasia, Kozlowski type

Summary

spondylometaphyseal dysplasia, Kozlowski type (MONDO:0008477) is a disease caused by TRPV4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: TRPV4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 128
• Phenotypes (HPO): 45

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0000925	Abnormality of the vertebral column	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002663	Delayed epiphyseal ossification	Very frequent (80-99%)
HP:0003521	Disproportionate short-trunk short stature	Very frequent (80-99%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001248	Short tubular bones of the hand	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001498	Carpal bone hypoplasia	Frequent (30-79%)
HP:0001831	Short toe	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002812	Coxa vara	Frequent (30-79%)
HP:0002867	Abnormality of the ilium	Frequent (30-79%)
HP:0002869	Flared iliac wings	Frequent (30-79%)
HP:0002970	Genu varum	Frequent (30-79%)
HP:0003016	Metaphyseal widening	Frequent (30-79%)
HP:0003088	Premature osteoarthritis	Frequent (30-79%)
HP:0003170	Abnormality of the acetabulum	Frequent (30-79%)
HP:0003177	Squared iliac bones	Frequent (30-79%)
HP:0003336	Abnormal enchondral ossification	Frequent (30-79%)
HP:0003510	Severe short stature	Frequent (30-79%)
HP:0005819	Short middle phalanx of finger	Frequent (30-79%)
HP:0009882	Short distal phalanx of finger	Frequent (30-79%)
HP:0010743	Short metatarsal	Frequent (30-79%)
HP:0000768	Pectus carinatum	Occasional (5-29%)
HP:0000914	Shield chest	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0002942	Thoracic kyphosis	Occasional (5-29%)
HP:0002986	Radial bowing	Occasional (5-29%)
HP:0003059	Abnormality of the radioulnar joints	Occasional (5-29%)
HP:0003121	Limb joint contracture	Occasional (5-29%)
HP:0003180	Flat acetabular roof	Occasional (5-29%)
HP:0003185	Short greater sciatic notch	Occasional (5-29%)
HP:0003311	Hypoplasia of the odontoid process	Occasional (5-29%)
HP:0003417	Coronal cleft vertebrae	Occasional (5-29%)
HP:0003907	Abnormality of the humeral metaphyses	Occasional (5-29%)
HP:0004558	Cervical platyspondyly	Occasional (5-29%)
HP:0008422	Vertebral wedging	Occasional (5-29%)
HP:0010228	Absent epiphyses of the phalanges of the hand	Occasional (5-29%)
HP:0030289	Flattened femoral epiphysis	Occasional (5-29%)
HP:0030320	Increased intervertebral space	Occasional (5-29%)
HP:0100864	Short femoral neck	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylometaphyseal dysplasia, Kozlowski type
Mondo ID	MONDO:0008477
MeSH	C535797
OMIM	184252
Orphanet	93314
DOID	DOID:0111554
ICD-11	360868302
UMLS	C0265280
MedGen	82698
GARD	0003047
Is cancer (heuristic)	no

Also known as: Dysmorphism arthrogryposis skeletal maturation advanced · Jequier Kozlowski skeletal dysplasia · Jequier-Kozlowski syndrome · skeletal dysplasia Jequier-Kozlowski type · SmD Kozlowski type · SMDK · spondylometaphyseal dysplasia, Kozlowski type

Data availability: 128 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 › skeletal dysplasia › spondylometaphyseal dysplasia › spondylometaphyseal dysplasia, Kozlowski type

Related subtypes (18): Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick 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

128 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 37 benign/likely benign, 30 conflicting classifications of pathogenicity, 13 benign, 5 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
126472	NM_021625.5(TRPV4):c.1851C>A (p.Phe617Leu)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18434	NM_021625.5(TRPV4):c.832G>A (p.Glu278Lys)	TRPV4	Pathogenic	criteria provided, single submitter
18435	NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
30472	NM_021625.5(TRPV4):c.694C>T (p.Arg232Cys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
4994	NM_021625.5(TRPV4):c.1781G>A (p.Arg594His)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4995	NM_021625.5(TRPV4):c.998A>G (p.Asp333Gly)	TRPV4	Pathogenic	no assertion criteria provided
4998	NM_021625.5(TRPV4):c.2396C>T (p.Pro799Leu)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
5000	NM_021625.5(TRPV4):c.806G>A (p.Arg269His)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215918	NM_021625.5(TRPV4):c.1546A>G (p.Ile516Val)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216733	NM_021625.5(TRPV4):c.2605G>A (p.Ala869Thr)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245716	NM_021625.5(TRPV4):c.37G>T (p.Gly13Trp)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245915	NM_021625.5(TRPV4):c.1139C>T (p.Thr380Met)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246534	NM_021625.5(TRPV4):c.1390C>T (p.Arg464Cys)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2724148	NM_021625.5(TRPV4):c.2461C>T (p.Arg821Cys)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282949	NM_021625.5(TRPV4):c.1491+10C>T	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307126	NM_021625.5(TRPV4):c.1825-15C>G	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307132	NM_021625.5(TRPV4):c.1211G>A (p.Arg404His)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307134	NM_021625.5(TRPV4):c.963C>A (p.Gly321=)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307138	NM_021625.5(TRPV4):c.650C>T (p.Ala217Val)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307143	NM_021625.5(TRPV4):c.205A>C (p.Met69Leu)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307144	NM_021625.5(TRPV4):c.171T>C (p.Pro57=)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
386671	NM_021625.5(TRPV4):c.1038C>T (p.Tyr346=)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409288	NM_021625.5(TRPV4):c.1976C>T (p.Ser659Leu)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
448711	NM_021625.5(TRPV4):c.523A>G (p.Thr175Ala)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469047	NM_021625.5(TRPV4):c.958C>T (p.Arg320Ter)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499138	NM_021625.5(TRPV4):c.2304G>C (p.Ser768=)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
517843	NM_021625.5(TRPV4):c.651G>A (p.Ala217=)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521109	NM_021625.5(TRPV4):c.1376T>G (p.Leu459Arg)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521669	NM_021625.5(TRPV4):c.1700A>T (p.Tyr567Phe)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
536854	NM_021625.5(TRPV4):c.2320C>T (p.Arg774Cys)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 9 · 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
TRPV4	Definitive	Autosomal dominant	metatropic dysplasia	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	gencc,clinvar
MIR4497	HGNC:41737	ENSG00000263510		microRNA 4497	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
MIR4497	Other/Unknown	no

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
cartilage tissue	1
lower esophagus mucosa	1
olfactory segment of nasal mucosa	1
blood	1
monocyte	1
myometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
MIR4497	29		yes	myometrium, monocyte, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRPV4	1,948
MIR4497	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPV4	Q9HBA0	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
TRP channels	1	407.9×	0.005	TRPV4
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.006	TRPV4

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
hyperosmotic salinity response	1	16852.0×	9e-04	TRPV4
blood vessel endothelial cell delamination	1	16852.0×	9e-04	TRPV4
vasopressin secretion	1	8426.0×	9e-04	TRPV4
positive regulation of striated muscle contraction	1	8426.0×	9e-04	TRPV4
regulation of response to osmotic stress	1	8426.0×	9e-04	TRPV4
calcium ion import into cytosol	1	8426.0×	9e-04	TRPV4
cellular hypotonic salinity response	1	5617.3×	0.001	TRPV4
positive regulation of macrophage inflammatory protein 1 alpha production	1	5617.3×	0.001	TRPV4
positive regulation of microtubule depolymerization	1	3370.4×	0.001	TRPV4
positive regulation of chemokine (C-C motif) ligand 5 production	1	2808.7×	0.001	TRPV4
negative regulation of brown fat cell differentiation	1	2808.7×	0.001	TRPV4
positive regulation of chemokine (C-X-C motif) ligand 1 production	1	2808.7×	0.001	TRPV4
cartilage development involved in endochondral bone morphogenesis	1	2407.4×	0.001	TRPV4
regulation of aerobic respiration	1	2106.5×	0.002	TRPV4
cortical microtubule organization	1	1872.4×	0.002	TRPV4
multicellular organismal-level water homeostasis	1	1685.2×	0.002	TRPV4
osmosensory signaling pathway	1	1532.0×	0.002	TRPV4
diet induced thermogenesis	1	1404.3×	0.002	TRPV4
cellular hypotonic response	1	1404.3×	0.002	TRPV4
positive regulation of vascular permeability	1	1296.3×	0.002	TRPV4
cellular response to osmotic stress	1	1203.7×	0.002	TRPV4
positive regulation of monocyte chemotactic protein-1 production	1	1203.7×	0.002	TRPV4
microtubule polymerization	1	887.0×	0.002	TRPV4
positive regulation of macrophage chemotaxis	1	802.5×	0.002	TRPV4
calcium ion import	1	802.5×	0.002	TRPV4
cell volume homeostasis	1	601.9×	0.003	TRPV4
calcium ion import across plasma membrane	1	543.6×	0.003	TRPV4
cell-cell junction assembly	1	443.5×	0.004	TRPV4
cellular response to heat	1	343.9×	0.005	TRPV4
response to mechanical stimulus	1	300.9×	0.005	TRPV4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPV4	6	3
MIR4497	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5

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

6 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.

Compound	Max phase	Cohort target (bioactivity)
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

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	1	TRPV4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MIR4497

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)
MIR4497	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.