Fibrochondrogenesis

Summary

Fibrochondrogenesis (MONDO:0016068) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 7
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000260	Wide anterior fontanel	Very frequent (80-99%)
HP:0000311	Round face	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000520	Proptosis	Very frequent (80-99%)
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0000773	Short ribs	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0000885	Broad ribs	Very frequent (80-99%)
HP:0000940	Abnormal diaphysis morphology	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001591	Bell-shaped thorax	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000364	Hearing abnormality	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000882	Hypoplastic scapulae	Frequent (30-79%)
HP:0001804	Hypoplastic fingernail	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001539	Omphalocele	Occasional (5-29%)
HP:0002983	Micromelia	Occasional (5-29%)
HP:0100490	Camptodactyly of finger	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	fibrochondrogenesis
Mondo ID	MONDO:0016068
MeSH	C562524
OMIM	228520
Orphanet	2021
DOID	DOID:0060465
ICD-11	1412541453
SNOMED CT	17144009
UMLS	C0265282
MedGen	82700
GARD	0002321
Is cancer (heuristic)	no

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 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 › fibrochondrogenesis

Related subtypes (49): atelosteogenesis, midface dysplasia, Kashin-Beck disease, achondroplasia, Boomerang dysplasia, campomelic dysplasia, cleidocranial dysplasia 1, Leri-Weill dyschondrosteosis, hypochondroplasia, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, Kniest dysplasia, pseudoachondroplasia, ulna metaphyseal dysplasia syndrome, acheiropody, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, bone dysplasia, lethal Holmgren type, cleidocranial dysplasia, recessive form, diastrophic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, lethal Kniest-like dysplasia, metaphyseal chondrodysplasia, Kaitila type, metaphyseal chondrodysplasia, Spahr type, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, pycnodysostosis, pyknoachondrogenesis, Pyle disease, schneckenbecken dysplasia, mesomelia-synostoses syndrome, lethal chondrodysplasia, Seller type, acrocapitofemoral dysplasia, brachyolmia, Desbuquois dysplasia, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, thanatophoric dysplasia, Blount disease, osteogenesis imperfecta, achondrogenesis, acromesomelic dysplasia, neonatal osteosclerotic dysplasia, Akaba Hayasaka syndrome, Fairbank disease, mesomelic dysplasia, spondyloepimetaphyseal dysplasia, cleidocranial dysplasia 2, arterial tortuosity-bone fragility syndrome, linkeropathy

Subtypes (2): fibrochondrogenesis 1, fibrochondrogenesis 2

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

7 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 3 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
29646	NM_001854.4(COL11A1):c.1786dup (p.Ala596fs)	COL11A1	Pathogenic	no assertion criteria provided
29648	NM_001854.4(COL11A1):c.2350G>C (p.Gly784Arg)	COL11A1	Pathogenic	no assertion criteria provided
29649	NM_001854.4(COL11A1):c.3943G>T (p.Gly1315Ter)	COL11A1	Pathogenic	criteria provided, single submitter
1021355	NM_001854.4(COL11A1):c.907G>A (p.Val303Ile)	COL11A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1395512	NM_001854.4(COL11A1):c.3263A>C (p.Glu1088Ala)	COL11A1	Uncertain significance	criteria provided, single submitter
2015216	NM_001854.4(COL11A1):c.4240G>T (p.Gly1414Cys)	COL11A1	Uncertain significance	criteria provided, single submitter
29647	NM_001854.4(COL11A1):c.3241G>C (p.Gly1081Arg)	COL11A1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 37 · Orphanet: 10 · 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
COL11A1	Definitive	Autosomal recessive	fibrochondrogenesis 1	17
COL11A2	Supportive	Autosomal dominant	fibrochondrogenesis	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	gencc,clinvar
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.

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)
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen

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
periodontal ligament	1
tibia	1
adenohypophysis	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
COL11A2	134	broad	yes	pituitary gland, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL11A1	2,433
COL11A2	1,583

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL11A1	P12107	53.06
COL11A2	P13942	50.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
MET activates PTK2 signaling	2	380.7×	4e-05	COL11A1, COL11A2
Collagen chain trimerization	2	259.6×	4e-05	COL11A1, COL11A2
Developmental Lineage of Pancreatic Ductal Cells	2	228.4×	4e-05	COL11A1, COL11A2
Assembly of collagen fibrils and other multimeric structures	2	200.3×	4e-05	COL11A1, COL11A2
Collagen degradation	2	175.7×	4e-05	COL11A1, COL11A2
Collagen biosynthesis and modifying enzymes	2	170.4×	4e-05	COL11A1, COL11A2
Non-integrin membrane-ECM interactions	2	154.3×	4e-05	COL11A1, COL11A2

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
collagen fibril organization	2	224.7×	3e-04	COL11A1, COL11A2
sensory perception of sound	2	100.9×	8e-04	COL11A1, COL11A2
tendon development	1	2106.5×	0.002	COL11A1
soft palate development	1	1685.2×	0.002	COL11A2
proteoglycan metabolic process	1	936.2×	0.003	COL11A1
chondrocyte development	1	468.1×	0.005	COL11A1
detection of mechanical stimulus involved in sensory perception of sound	1	468.1×	0.005	COL11A1
cartilage condensation	1	383.0×	0.005	COL11A1
ventricular cardiac muscle tissue morphogenesis	1	351.1×	0.005	COL11A1
endodermal cell differentiation	1	247.8×	0.006	COL11A1
embryonic skeletal system morphogenesis	1	195.9×	0.007	COL11A1
inner ear morphogenesis	1	150.5×	0.009	COL11A1
cartilage development	1	125.8×	0.009	COL11A2
roof of mouth development	1	123.9×	0.009	COL11A2
skeletal system development	1	62.9×	0.017	COL11A2
visual perception	1	39.8×	0.025	COL11A1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL11A1	0	0
COL11A2	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	COL11A1, COL11A2

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)
COL11A1	0	—
COL11A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.