Stapes ankylosis with broad thumbs and toes

Summary

Stapes ankylosis with broad thumbs and toes (MONDO:0008484) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	stapes ankylosis with broad thumbs and toes
Mondo ID	MONDO:0008484
OMIM	184460
Orphanet	140917
ICD-11	387089262
SNOMED CT	719305006
UMLS	C1866656
MedGen	357104
GARD	0012631
Is cancer (heuristic)	no

Also known as: Teunissen-Cremers syndrome

Data availability: 9 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › symphalangism › NOG-related symphalangism spectrum disorder › stapes ankylosis with broad thumbs and toes

Related subtypes (4): multiple synostoses syndrome 1, tarsal-carpal coalition syndrome, brachydactyly type B2, proximal symphalangism 1A

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

9 retrieved; paginated sample, class counts are floors:

5 pathogenic, 2 likely pathogenic, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
987739	Single allele	ANKFN1	Pathogenic	no assertion criteria provided
3250390	NM_005450.6(NOG):c.613dup (p.Trp205fs)	NOG	Pathogenic	criteria provided, single submitter
6703	NM_005450.6(NOG):c.103C>T (p.Pro35Ser)	NOG	Pathogenic	criteria provided, single submitter
6704	NM_005450.6(NOG):c.328C>T (p.Gln110Ter)	NOG	Pathogenic	criteria provided, multiple submitters, no conflicts
6705	NM_005450.6(NOG):c.252dup (p.Glu85fs)	NOG	Pathogenic	no assertion criteria provided
2663770	NM_005450.6(NOG):c.553T>C (p.Ser185Pro)	NOG	Likely pathogenic	criteria provided, single submitter
3382219	NM_005450.6(NOG):c.509del (p.Pro170fs)	NOG	Likely pathogenic	criteria provided, single submitter
375295	NM_005450.6(NOG):c.611G>A (p.Arg204Gln)	NOG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3382452	NM_005450.6(NOG):c.545G>C (p.Arg182Pro)	NOG	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
NOG	Supportive	Autosomal dominant	stapes ankylosis with broad thumbs and toes	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOG	Orphanet:140908	Brachydactyly type B2
NOG	Orphanet:140917	Stapes ankylosis with broad thumbs and toes
NOG	Orphanet:1412	Tarsal-carpal coalition syndrome
NOG	Orphanet:3237	Multiple synostoses syndrome
NOG	Orphanet:3250	Proximal symphalangism

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
NOG	HGNC:7866	ENSG00000183691	Q13253	Noggin	gencc,clinvar
ANKFN1	HGNC:26766	ENSG00000153930	Q8N957	Ankyrin repeat and fibronectin type-III domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOG	Noggin	Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite.
ANKFN1	Ankyrin repeat and fibronectin type-III domain-containing protein 1	May play a role in neuronal function.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOG	Other/Unknown	no		Noggin, Cystine-knot_cytokine
ANKFN1	Antibody/Immunoglobulin	yes		Ankyrin_rpt, FN3_dom, Ig-like_fold

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
buccal mucosa cell	2
male germ line stem cell (sensu Vertebrata) in testis	2
pigmented layer of retina	1
bronchial epithelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOG	155	broad	marker	pigmented layer of retina, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis
ANKFN1	148	tissue_specific	marker	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOG	2,338
ANKFN1	601

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOG	Q13253	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKFN1	Q8N957	66.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Formation of paraxial mesoderm	1	407.9×	0.003	NOG
Signaling by BMP	1	356.9×	0.003	NOG

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
regulation of establishment of bipolar cell polarity	1	8426.0×	0.004	ANKFN1
negative regulation of cardiac epithelial to mesenchymal transition	1	8426.0×	0.004	NOG
positive regulation of glomerulus development	1	4213.0×	0.004	NOG
neural plate morphogenesis	1	2808.7×	0.004	NOG
cell differentiation in hindbrain	1	2808.7×	0.004	NOG
neural plate anterior/posterior regionalization	1	2808.7×	0.004	NOG
short-term synaptic potentiation	1	2808.7×	0.004	NOG
prostatic bud formation	1	2106.5×	0.004	NOG
axial mesoderm development	1	1685.2×	0.004	NOG
notochord morphogenesis	1	1685.2×	0.004	NOG
ventricular compact myocardium morphogenesis	1	1203.7×	0.004	NOG
regulation of fibroblast growth factor receptor signaling pathway	1	1203.7×	0.004	NOG
equilibrioception	1	1203.7×	0.004	ANKFN1
atrial cardiac muscle tissue morphogenesis	1	1203.7×	0.004	NOG
ureteric bud formation	1	1203.7×	0.004	NOG
negative regulation of cartilage development	1	1053.2×	0.004	NOG
negative regulation of cardiac muscle cell proliferation	1	936.2×	0.004	NOG
heart trabecula morphogenesis	1	936.2×	0.004	NOG
membranous septum morphogenesis	1	842.6×	0.004	NOG
pharyngeal arch artery morphogenesis	1	842.6×	0.004	NOG
negative regulation of astrocyte differentiation	1	766.0×	0.004	NOG
embryonic skeletal joint morphogenesis	1	766.0×	0.004	NOG
endoderm formation	1	702.2×	0.004	NOG
endocardial cushion formation	1	702.2×	0.004	NOG
nodal signaling pathway	1	561.7×	0.005	NOG
somite development	1	561.7×	0.005	NOG
locomotor rhythm	1	526.6×	0.005	ANKFN1
lung morphogenesis	1	526.6×	0.005	NOG
cranial skeletal system development	1	468.1×	0.006	NOG
positive regulation of branching involved in ureteric bud morphogenesis	1	401.2×	0.006	NOG

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
NOG	0	0
ANKFN1	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	1	ANKFN1
E	Difficult family or no structure, no drug	1	NOG

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)
NOG	0	—
ANKFN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.