Metaphyseal chondrodysplasia

Summary

Metaphyseal chondrodysplasia (MONDO:0000138) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	metaphyseal chondrodysplasia
Mondo ID	MONDO:0000138
SNOMED CT	28681006
UMLS	C0265290
MedGen	120528
GARD	0022714
Is cancer (heuristic)	no

Also known as: metaphyseal chondrodysplasia · metaphyseal chondrodysplasia (disease)

Data availability: 2 ClinVar variants · 1 HPO phenotype.

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 › Pyle disease › metaphyseal chondrodysplasia

Related subtypes (1): chondrodysplasia calcificans Metaphysealis

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
430150	NM_000138.5(FBN1):c.5183C>T (p.Ala1728Val)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438461	NM_014112.5(TRPS1):c.2732A>G (p.Asn911Ser)	TRPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPS1	Orphanet:502	Trichorhinophalangeal syndrome type 2
TRPS1	Orphanet:77258	Trichorhinophalangeal syndrome type 1
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia

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
TRPS1	HGNC:12340	ENSG00000104447	Q9UHF7	Zinc finger transcription factor Trps1	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPS1	Zinc finger transcription factor Trps1	Transcriptional repressor.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPS1	Transcription factor	no		Znf_GATA, Znf_C2H2_type, Znf_NHR/GATA
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
calcaneal tendon	1
epithelium of mammary gland	1
mammary duct	1
decidua	1
skin of hip	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPS1	284	ubiquitous	marker	mammary duct, epithelium of mammary gland, calcaneal tendon
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640
TRPS1	2,588

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRPS1	Q9UHF7	49.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Elastic fibre formation	1	335.9×	0.008	FBN1
TGF-beta receptor signaling activates SMADs	1	326.3×	0.008	FBN1
Molecules associated with elastic fibres	1	308.6×	0.008	FBN1
Integrin cell surface interactions	1	134.3×	0.012	FBN1
Degradation of the extracellular matrix	1	117.7×	0.012	FBN1
Post-translational protein phosphorylation	1	100.2×	0.012	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	FBN1

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
skeletal system development	2	125.8×	0.001	TRPS1, FBN1
post-embryonic eye morphogenesis	1	2808.7×	0.002	FBN1
obsolete sequestering of BMP in extracellular matrix	1	2106.5×	0.002	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	2106.5×	0.002	FBN1
negative regulation of osteoclast development	1	1685.2×	0.002	FBN1
embryonic eye morphogenesis	1	766.0×	0.004	FBN1
regulation of chondrocyte differentiation	1	702.2×	0.004	TRPS1
cellular response to insulin-like growth factor stimulus	1	648.1×	0.004	FBN1
cell adhesion mediated by integrin	1	337.0×	0.007	FBN1
negative regulation of osteoclast differentiation	1	271.8×	0.007	FBN1
metanephros development	1	255.3×	0.007	FBN1
camera-type eye development	1	179.3×	0.009	FBN1
lung alveolus development	1	175.5×	0.009	FBN1
cellular response to transforming growth factor beta stimulus	1	138.1×	0.010	FBN1
glucose metabolic process	1	127.7×	0.010	FBN1
glucose homeostasis	1	65.3×	0.019	FBN1
gene expression	1	39.9×	0.028	FBN1
heart development	1	39.4×	0.028	FBN1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.115	TRPS1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	TRPS1

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
TRPS1	0	0
FBN1	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	TRPS1, FBN1

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)
TRPS1	0	—
FBN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.