Craniometaphyseal dysplasia, autosomal dominant

Summary

Craniometaphyseal dysplasia, autosomal dominant (MONDO:0007397) is a disease caused by ANKH (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: ANKH (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 211
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	craniometaphyseal dysplasia, autosomal dominant
Mondo ID	MONDO:0007397
MeSH	C565145
OMIM	123000
DOID	DOID:0080801
UMLS	C1852502
MedGen	338945
GARD	0001581
Is cancer (heuristic)	no

Also known as: CMD · CMDD · CMDJ · craniometaphyseal dysplasia Jackson type · craniometaphyseal dysplasia, autosomal dominant

Data availability: 211 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 › craniometaphyseal dysplasia, autosomal dominant

Related subtypes (3): 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

ClinVar germline variants

211 retrieved; paginated sample, class counts are floors:

91 uncertain significance, 75 benign, 21 benign/likely benign, 12 conflicting classifications of pathogenicity, 5 pathogenic, 3 likely benign, 2 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3340533	NM_054027.6(ANKH):c.1261dup (p.Leu421fs)	ANKH	Pathogenic	criteria provided, single submitter
5191	NM_054027.6(ANKH):c.1126TTC[1] (p.Phe377del)	ANKH	Pathogenic	criteria provided, multiple submitters, no conflicts
5193	NM_054027.6(ANKH):c.1142-4A>G	ANKH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5194	NM_054027.6(ANKH):c.1124_1126del (p.Ser375del)	ANKH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5200	NM_054027.6(ANKH):c.1015T>C (p.Cys339Arg)	ANKH	Pathogenic	no assertion criteria provided
5201	NM_054027.6(ANKH):c.1172T>C (p.Leu391Pro)	ANKH	Pathogenic	no assertion criteria provided
5202	NM_054027.6(ANKH):c.1001T>G (p.Leu334Arg)	ANKH	Pathogenic	no assertion criteria provided
2627751	NM_054027.6(ANKH):c.314-2A>T	ANKH	Likely pathogenic	criteria provided, single submitter
5192	NM_054027.6(ANKH):c.1165G>A (p.Gly389Arg)	ANKH	Likely pathogenic	criteria provided, single submitter
199179	NM_054027.6(ANKH):c.1141+5A>G	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351393	NM_054027.6(ANKH):c.*6012T>C	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351504	NM_054027.6(ANKH):c.1115G>A (p.Arg372Gln)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351505	NM_054027.6(ANKH):c.1071C>T (p.Ile357=)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351543	NM_054027.6(ANKH):c.585C>T (p.Leu195=)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903973	NM_054027.6(ANKH):c.1021G>A (p.Val341Met)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904041	NM_054027.6(ANKH):c.1000C>G (p.Leu334Val)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904225	NM_054027.6(ANKH):c.600C>T (p.Gly200=)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905082	NM_054027.6(ANKH):c.156C>T (p.Tyr52=)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905793	NM_054027.6(ANKH):c.1357C>T (p.Arg453Trp)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906300	NM_054027.6(ANKH):c.1304C>T (p.Ala435Val)	ANKH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351433	NM_054027.6(ANKH):c.*3616C>T	OTULIN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
351388	NM_054027.6(ANKH):c.*6205G>A	ANKH	Uncertain significance	criteria provided, single submitter
351390	NM_054027.6(ANKH):c.*6129G>A	ANKH	Uncertain significance	criteria provided, single submitter
351391	NM_054027.6(ANKH):c.*6041T>C	ANKH	Uncertain significance	criteria provided, single submitter
351392	NM_054027.6(ANKH):c.*6034A>C	ANKH	Uncertain significance	criteria provided, single submitter
351396	NM_054027.6(ANKH):c.*5912T>A	ANKH	Uncertain significance	criteria provided, single submitter
351397	NM_054027.6(ANKH):c.*5898G>A	ANKH	Uncertain significance	criteria provided, single submitter
351398	NM_054027.6(ANKH):c.*5895C>G	ANKH	Uncertain significance	criteria provided, single submitter
351401	NM_054027.6(ANKH):c.*5725G>T	ANKH	Uncertain significance	criteria provided, single submitter
351404	NM_054027.6(ANKH):c.*5593G>C	ANKH	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKH	Orphanet:1416	Familial calcium pyrophosphate deposition
ANKH	Orphanet:1522	Craniometaphyseal dysplasia
OTULIN	Orphanet:500062	Infantile-onset periodic fever-panniculitis-dermatosis syndrome

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,clinvar
OTULIN	HGNC:25118	ENSG00000154124	Q96BN8	Ubiquitin thioesterase otulin	clinvar

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.
OTULIN	Ubiquitin thioesterase otulin	Deubiquitinase that specifically removes linear (‘Met-1’-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response.

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
OTULIN	Other/Unknown	no		FAM105, Otulin

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
bone marrow cell	1
buccal mucosa cell	1
pancreatic ductal cell	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
OTULIN	234	ubiquitous	marker	buccal mucosa cell, bone marrow cell, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OTULIN	1,553
ANKH	850

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OTULIN	Q96BN8	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKH	Q9HCJ1	84.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Miscellaneous transport and binding events	1	219.6×	0.011	ANKH
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	184.2×	0.011	OTULIN
Regulation of TNFR1 signaling	1	112.0×	0.012	OTULIN
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
protein linear deubiquitination	1	2808.7×	0.005	OTULIN
inhibition of non-skeletal tissue mineralization	1	2106.5×	0.005	ANKH
diphosphate metabolic process	1	1685.2×	0.005	ANKH
cementum mineralization	1	1203.7×	0.005	ANKH
response to sodium phosphate	1	842.6×	0.005	ANKH
ATP export	1	842.6×	0.005	ANKH
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	766.0×	0.005	OTULIN
phosphate ion transmembrane transport	1	601.9×	0.005	ANKH
phosphate ion homeostasis	1	526.6×	0.005	ANKH
regulation of bone mineralization	1	366.4×	0.007	ANKH
regulation of tumor necrosis factor-mediated signaling pathway	1	351.1×	0.007	OTULIN
muscle cell cellular homeostasis	1	324.1×	0.007	ANKH
regulation of canonical Wnt signaling pathway	1	271.8×	0.007	OTULIN
sprouting angiogenesis	1	240.7×	0.008	OTULIN
calcium ion homeostasis	1	221.7×	0.008	ANKH
obsolete negative regulation of NF-kappaB transcription factor activity	1	179.3×	0.009	OTULIN
bone mineralization	1	135.9×	0.011	ANKH
locomotory behavior	1	89.6×	0.016	ANKH
transmembrane transport	1	84.3×	0.016	ANKH
negative regulation of inflammatory response	1	68.5×	0.019	OTULIN
skeletal system development	1	62.9×	0.020	ANKH
Wnt signaling pathway	1	49.9×	0.024	OTULIN
gene expression	1	39.9×	0.028	ANKH
protein ubiquitination	1	20.7×	0.052	OTULIN
proteolysis	1	17.1×	0.059	OTULIN
innate immune response	1	16.8×	0.059	OTULIN

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
ANKH	0	0
OTULIN	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	ANKH, OTULIN

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)
ANKH	0	—
OTULIN	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
NCT06529848	Not specified	RECRUITING	Impact of Exercise Training on Ischemia With Non-Obstructive Coronary Arteries (INOCA): The ExINOCA Study