Craniometaphyseal dysplasia

Summary

Craniometaphyseal dysplasia (MONDO:0015465) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• Phenotypes (HPO): 13
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		160	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0004493	Craniofacial hyperostosis	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0011002	Osteopetrosis	Very frequent (80-99%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0002652	Skeletal dysplasia	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0001291	Abnormal cranial nerve morphology	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	craniometaphyseal dysplasia
Mondo ID	MONDO:0015465
OMIM	123000
Orphanet	1522
DOID	DOID:0080033
ICD-11	305860050
SNOMED CT	36601008
UMLS	C0265292
MedGen	82702
GARD	0015013
NORD	1013
Is cancer (heuristic)	no

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › osteosclerosis › familial osteosclerosis › craniometaphyseal dysplasia

Related subtypes (2): axial osteomalacia, osteopetrosis

Subtypes (4): craniometaphyseal dysplasia, autosomal dominant, craniodiaphyseal dysplasia, craniometaphyseal dysplasia, autosomal recessive, craniodiaphyseal dysplasia, autosomal dominant

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 36 · 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
ANKH	Definitive	Autosomal dominant	craniometaphyseal dysplasia, autosomal dominant	11
GJA1	Definitive	Autosomal dominant	oculodentodigital dysplasia	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKH	Orphanet:1416	Familial calcium pyrophosphate deposition
ANKH	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:1010	Autosomal dominant palmoplantar keratoderma and congenital alopecia
GJA1	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:2248	Hypoplastic left heart syndrome
GJA1	Orphanet:2710	Oculodentodigital dysplasia
GJA1	Orphanet:317	Erythrokeratodermia variabilis
GJA1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJA1	Orphanet:93404	Syndactyly type 3

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
ANKH	HGNC:15492	ENSG00000154122	Q9HCJ1	Mineralization regulator ANKH	gencc
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANKH	Mineralization regulator ANKH	Transports adenosine triphosphate (ATP) and possibly other nucleoside triphosphates (NTPs) from cytosol to the extracellular space.
GJA1	Gap junction alpha-1 protein	Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between…

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)
ANKH	Other/Unknown	no		ANKH
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N

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
inferior vagus X ganglion	1
parotid gland	1
tibia	1
dorsal motor nucleus of vagus nerve	1
hair follicle	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKH	273	ubiquitous	marker	tibia, parotid gland, inferior vagus X ganglion
GJA1	292	ubiquitous	marker	lateral globus pallidus, dorsal motor nucleus of vagus nerve, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJA1	4,942
ANKH	850

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJA1	P17302	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKH	Q9HCJ1	84.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Oligomerization of connexins into connexons	1	1903.3×	0.002	GJA1
Transport of connexins along the secretory pathway	1	1903.3×	0.002	GJA1
Regulation of gap junction activity	1	1903.3×	0.002	GJA1
SARS-CoV-2 targets PDZ proteins in cell-cell junction	1	1142.0×	0.003	GJA1
Formation of annular gap junctions	1	519.1×	0.005	GJA1
Gap junction degradation	1	475.8×	0.005	GJA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	335.9×	0.006	GJA1
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	271.9×	0.006	GJA1
Miscellaneous transport and binding events	1	219.6×	0.007	ANKH
Gap junction assembly	1	146.4×	0.009	GJA1
RHOJ GTPase cycle	1	100.2×	0.012	GJA1
RHOQ GTPase cycle	1	90.6×	0.012	GJA1
Transport of small molecules	1	12.6×	0.078	ANKH

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
microtubule-based transport	1	8426.0×	0.003	GJA1
positive regulation of mesodermal cell differentiation	1	8426.0×	0.003	GJA1
negative regulation of gonadotropin secretion	1	4213.0×	0.004	GJA1
positive regulation of morphogenesis of an epithelium	1	2808.7×	0.004	GJA1
cell communication by electrical coupling	1	2106.5×	0.004	GJA1
inhibition of non-skeletal tissue mineralization	1	2106.5×	0.004	ANKH
diphosphate metabolic process	1	1685.2×	0.004	ANKH
cementum mineralization	1	1203.7×	0.004	ANKH
negative regulation of trophoblast cell migration	1	1203.7×	0.004	GJA1
gap junction assembly	1	1053.2×	0.004	GJA1
glutamate secretion	1	842.6×	0.004	GJA1
atrial cardiac muscle cell action potential	1	842.6×	0.004	GJA1
export across plasma membrane	1	842.6×	0.004	GJA1
response to sodium phosphate	1	842.6×	0.004	ANKH
ATP export	1	842.6×	0.004	ANKH
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.004	GJA1
phosphate ion transmembrane transport	1	601.9×	0.004	ANKH
cardiac conduction system development	1	526.6×	0.004	GJA1
phosphate ion homeostasis	1	526.6×	0.004	ANKH
bone remodeling	1	468.1×	0.005	GJA1
xenobiotic transport	1	421.3×	0.005	GJA1
regulation of bone mineralization	1	366.4×	0.006	ANKH
muscle cell cellular homeostasis	1	324.1×	0.006	ANKH
positive regulation of stem cell proliferation	1	263.3×	0.007	GJA1
establishment of mitotic spindle orientation	1	240.7×	0.007	GJA1
maintenance of blood-brain barrier	1	240.7×	0.007	GJA1
calcium ion homeostasis	1	221.7×	0.007	ANKH
positive regulation of vascular associated smooth muscle cell proliferation	1	216.1×	0.007	GJA1
cellular response to amyloid-beta	1	195.9×	0.008	GJA1
bone development	1	138.1×	0.011	GJA1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJA1	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJA1	1	4
ANKH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GJA1	4	Binding:4

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

1 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)
KANAMYCIN	4	GJA1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJA1
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	1	ANKH

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)
ANKH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01630460	Not specified	RECRUITING	Genetic and Functional Analysis of Craniometaphyseal Dysplasia (CMD)