Spondyloepiphyseal dysplasia tarda

Summary

Spondyloepiphyseal dysplasia tarda (MONDO:0019667) is a disease (an umbrella term covering 6 Mondo subtypes) with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 71
• Phenotypes (HPO): 54

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001552	Barrel-shaped chest	Very frequent (80-99%)
HP:0002654	Multiple epiphyseal dysplasia	Very frequent (80-99%)
HP:0003051	Enlarged metaphyses	Very frequent (80-99%)
HP:0003088	Premature osteoarthritis	Very frequent (80-99%)
HP:0003521	Disproportionate short-trunk short stature	Very frequent (80-99%)
HP:0004594	Hump-shaped mound of bone in central and posterior portions of vertebral endplate	Very frequent (80-99%)
HP:0005775	Multiple skeletal anomalies	Very frequent (80-99%)
HP:0012771	Increased arm span	Very frequent (80-99%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0001386	Joint swelling	Frequent (30-79%)
HP:0002763	Abnormal cartilage morphology	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0002945	Intervertebral space narrowing	Frequent (30-79%)
HP:0003043	Abnormality of the shoulder	Frequent (30-79%)
HP:0003365	Arthralgia of the hip	Frequent (30-79%)
HP:0003418	Back pain	Frequent (30-79%)
HP:0003855	Spurred metaphyses of the upper limbs	Frequent (30-79%)
HP:0005086	Knee osteoarthritis	Frequent (30-79%)
HP:0008843	Hip osteoarthritis	Frequent (30-79%)
HP:0010656	Abnormal epiphyseal ossification	Frequent (30-79%)
HP:0011001	Increased bone mineral density	Frequent (30-79%)
HP:0030839	Knee pain	Frequent (30-79%)
HP:0100569	Abnormally ossified vertebrae	Frequent (30-79%)
HP:0100712	Abnormal lumbar spine morphology	Frequent (30-79%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002812	Coxa vara	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0002942	Thoracic kyphosis	Occasional (5-29%)
HP:0002996	Limited elbow movement	Occasional (5-29%)
HP:0003311	Hypoplasia of the odontoid process	Occasional (5-29%)
HP:0003832	Abnormality of the tibial plateaux	Occasional (5-29%)
HP:0004586	Biconcave vertebral bodies	Occasional (5-29%)
HP:0004637	Decreased cervical spine mobility	Occasional (5-29%)
HP:0006233	Osteoarthritis of the distal interphalangeal joint	Occasional (5-29%)
HP:0006248	Limited wrist movement	Occasional (5-29%)
HP:0006467	Limited shoulder movement	Occasional (5-29%)
HP:0008812	Flattened femoral head	Occasional (5-29%)
HP:0009763	Limb pain	Occasional (5-29%)
HP:0010231	Enlarged epiphyses of the phalanges of the hand	Occasional (5-29%)
HP:0010575	Dysplasia of the femoral head	Occasional (5-29%)
HP:0025131	Finger swelling	Occasional (5-29%)
HP:0025263	Stiff knee	Occasional (5-29%)
HP:0040161	Localized osteoporosis	Occasional (5-29%)
HP:0100864	Short femoral neck	Occasional (5-29%)
HP:0000175	Cleft palate	Excluded (0%)
HP:0000541	Retinal detachment	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepiphyseal dysplasia tarda
Mondo ID	MONDO:0019667
Orphanet	93284
DOID	DOID:0112284
SNOMED CT	51952004
GARD	0025144
NORD	1732
Is cancer (heuristic)	no

Data availability: 71 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 6 Mondo subtypes.

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 tarda

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, Kimberley type, 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, 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

Subtypes (6): spondyloepiphyseal dysplasia tarda, autosomal dominant, spondyloepiphyseal dysplasia tarda, autosomal recessive, spondyloepiphyseal dysplasia tarda, Kohn type, spondyloepiphyseal dysplasia tarda, X-linked, spondyloepiphyseal dysplasia tarda with characteristic facies, spondyloepiphyseal dysplasia tarda, autosomal recessive, Leroy-Spranger 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

71 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 17 benign, 14 pathogenic, 5 likely benign, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11507	NM_001011658.4(TRAPPC2):c.53_54del (p.Val17_Phe18insTer)	OFD1	Pathogenic	no assertion criteria provided
11508	NM_001011658.4(TRAPPC2):c.191_192del (p.Val64fs)	OFD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11509	NM_001011658.4(TRAPPC2):c.157_158del (p.Met53fs)	OFD1	Pathogenic	no assertion criteria provided
11510	NM_001011658.4(TRAPPC2):c.271_275del (p.Gln91fs)	OFD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11512	NM_001011658.4(TRAPPC2):c.93+5G>A	OFD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11516	NM_001011658.4(TRAPPC2):c.238+4T>C	OFD1	Pathogenic	no assertion criteria provided
127114	NM_001011658.4(TRAPPC2):c.239-11_239-9del	OFD1	Pathogenic	no assertion criteria provided
623471	NM_001011658.4(TRAPPC2):c.1A>T (p.Met1Leu)	OFD1	Pathogenic	no assertion criteria provided
623472	NM_001011658.4(TRAPPC2):c.40del (p.Asp14fs)	OFD1	Pathogenic	no assertion criteria provided
694600	NM_001011658.4(TRAPPC2):c.216_217del (p.Ser73fs)	OFD1	Pathogenic	criteria provided, single submitter
804351	NM_001011658.4(TRAPPC2):c.241_242del (p.Met81fs)	OFD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11514	NM_001011658.4(TRAPPC2):c.391C>T (p.Gln131Ter)	TRAPPC2	Pathogenic	no assertion criteria provided
11515	NM_001011658.4(TRAPPC2):c.329C>A (p.Ser110Ter)	TRAPPC2	Pathogenic	no assertion criteria provided
11517	NM_001011658.4(TRAPPC2):c.387del (p.Val130fs)	TRAPPC2	Pathogenic	no assertion criteria provided
11513	NM_001011658.4(TRAPPC2):c.248T>C (p.Phe83Ser)	OFD1	Likely pathogenic	criteria provided, single submitter
997993	NM_001011658.4(TRAPPC2):c.324+1G>T	OFD1	Likely pathogenic	no assertion criteria provided
3384073	NM_001011658.4(TRAPPC2):c.391_392del (p.Gln131fs)	TRAPPC2	Likely pathogenic	criteria provided, single submitter
212743	NM_001011658.4(TRAPPC2):c.-97G>A	OFD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912339	NM_001011658.4(TRAPPC2):c.*263T>C	TRAPPC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367996	NM_001011658.4(TRAPPC2):c.-179G>C	LOC126863212	Uncertain significance	criteria provided, single submitter
931726	NM_001011658.4(TRAPPC2):c.176T>C (p.Met59Thr)	OFD1	Uncertain significance	criteria provided, single submitter
367965	NM_001011658.4(TRAPPC2):c.*2060G>A	TRAPPC2	Uncertain significance	criteria provided, single submitter
367972	NM_001011658.4(TRAPPC2):c.*1191C>T	TRAPPC2	Uncertain significance	criteria provided, single submitter
367979	NM_001011658.4(TRAPPC2):c.*942G>T	TRAPPC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
367982	NM_001011658.4(TRAPPC2):c.*752A>G	TRAPPC2	Uncertain significance	criteria provided, single submitter
367984	NM_001011658.4(TRAPPC2):c.*703G>A	TRAPPC2	Uncertain significance	criteria provided, single submitter
367987	NM_001011658.4(TRAPPC2):c.*465T>G	TRAPPC2	Uncertain significance	criteria provided, single submitter
367988	NM_001011658.4(TRAPPC2):c.*435A>G	TRAPPC2	Uncertain significance	criteria provided, single submitter
367991	NM_001011658.4(TRAPPC2):c.*323T>G	TRAPPC2	Uncertain significance	criteria provided, single submitter
367994	NM_001011658.4(TRAPPC2):c.*243G>T	TRAPPC2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
TRAPPC2	Definitive	X-linked	spondyloepiphyseal dysplasia tarda, X-linked	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRAPPC2	Orphanet:93284	Spondyloepiphyseal dysplasia tarda
OFD1	Orphanet:244	Primary ciliary dyskinesia
OFD1	Orphanet:2750	Orofaciodigital syndrome type 1
OFD1	Orphanet:2754	Orofaciodigital syndrome type 6
OFD1	Orphanet:475	Isolated Joubert syndrome
OFD1	Orphanet:791	Retinitis pigmentosa

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
TRAPPC2	HGNC:23068	ENSG00000196459	P0DI81	Trafficking protein particle complex subunit 2	gencc,clinvar
OFD1	HGNC:2567	ENSG00000046651	O75665	Centriole and centriolar satellite protein OFD1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRAPPC2	Trafficking protein particle complex subunit 2	Prevents transcriptional repression and induction of cell death by ENO1.
OFD1	Centriole and centriolar satellite protein OFD1	Component of the centrioles controlling mother and daughter centrioles length.

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)
TRAPPC2	Other/Unknown	no		Sedlin, Longin-like_dom_sf
OFD1	Other/Unknown	no		LisH, OFD1

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar vermis	1
cortical plate	1
bronchial epithelial cell	1
cervix squamous epithelium	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRAPPC2	279	ubiquitous	marker	cortical plate, cerebellar vermis, cerebellar cortex
OFD1	288	ubiquitous	marker	sperm, bronchial epithelial cell, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OFD1	2,878
TRAPPC2	1,220

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRAPPC2	P0DI81	92.44
OFD1	O75665	68.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Hedgehog ‘off’ state	1	89.2×	0.018	OFD1
COPII-mediated vesicle transport	1	81.6×	0.018	TRAPPC2
Loss of Nlp from mitotic centrosomes	1	79.3×	0.018	OFD1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.018	OFD1
AURKA Activation by TPX2	1	76.1×	0.018	OFD1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.018	OFD1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.018	OFD1
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.018	TRAPPC2
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.018	OFD1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.018	OFD1

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
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	4213.0×	0.002	OFD1
embryonic body morphogenesis	1	1053.2×	0.004	OFD1
vesicle coat assembly	1	766.0×	0.004	TRAPPC2
epithelial cilium movement involved in determination of left/right asymmetry	1	648.1×	0.004	OFD1
obsolete vesicle tethering	1	495.6×	0.004	TRAPPC2
COPII vesicle coat assembly	1	351.1×	0.005	TRAPPC2
axoneme assembly	1	271.8×	0.005	OFD1
endoplasmic reticulum to Golgi vesicle-mediated transport	1	68.0×	0.018	TRAPPC2
skeletal system development	1	62.9×	0.018	TRAPPC2
cilium assembly	1	36.8×	0.027	OFD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
TRAPPC2	0	0
OFD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	TRAPPC2, OFD1

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)
TRAPPC2	0	—
OFD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.