Tarsal-carpal coalition syndrome

Summary

Tarsal-carpal coalition syndrome (MONDO:0008521) is a disease with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include sodium chloride.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 3
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0003028	Abnormality of the ankles	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0008368	Tarsal synostosis	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tarsal-carpal coalition syndrome
Mondo ID	MONDO:0008521
OMIM	186570
Orphanet	1412
DOID	DOID:0050789
ICD-11	1118132902
SNOMED CT	702312009
UMLS	C1861305
MedGen	348322
GARD	0009225
Is cancer (heuristic)	no

Also known as: tarsal carpal coalition syndrome · tarsal-carpal coalition syndrome · TCC

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › congenital limb malformation › tarsal-carpal coalition syndrome

Related subtypes (106): Adams-Oliver syndrome, ADULT syndrome, Hypoglossia-hypodactyly syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Cooks syndrome, Townes-Brocks syndrome, brachydactyly-arterial hypertension syndrome, brachydactyly-preaxial hallux varus syndrome, fibular aplasia-ectrodactyly syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, femoral-facial syndrome, laurin-Sandrow syndrome, Emery-Nelson syndrome, hand-foot-genital syndrome, IVIC syndrome, Leri pleonosteosis, OSLAM syndrome, pelvis-shoulder dysplasia, phocomelia-ectrodactyly-deafness-sinus arrhythmia syndrome, Poland syndrome, crossed polysyndactyly, postaxial tetramelic oligodactyly, radio-renal syndrome, scalp defects-postaxial polydactyly syndrome, splenogonadal fusion-limb defects-micrognathia syndrome, Karsch-Neugebauer syndrome, symphalangism with multiple anomalies of hands and feet, proximal symphalangism, extensor tendons of finger anomalies, tetramelic monodactyly, thumb stiffness-brachydactyly-intellectual disability syndrome, tibia, hypoplasia or aplasia of, with polydactyly, Say-field-Coldwell syndrome, triphalangeal thumbs-brachyectrodactyly syndrome, humerus trochlea aplasia, Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome, camptodactyly syndrome, Guadalajara type 2, Cenani-Lenz syndactyly syndrome, split hand-foot malformation 1 with sensorineural hearing loss, EEM syndrome, ectrodactyly-polydactyly syndrome, lethal faciocardiomelic dysplasia, femur-fibula-ulna complex, Gollop-Wolfgang complex, acromesomelic dysplasia 2B, Fuhrmann syndrome, hallux varus-preaxial polysyndactyly syndrome, Keutel syndrome, absence deformity of leg-cataract syndrome, intellectual disability-spasticity-ectrodactyly syndrome, fibular aplasia, tibial campomelia, and oligosyndactyly syndrome, pelviscapular dysplasia, radioulnar synostosis-developmental delay-hypotonia syndrome, rapadilino syndrome, EEC syndrome, Sugarman brachydactyly, tetraamelia-multiple malformations syndrome, thrombocytopenia-absent radius syndrome, phocomelia, Schinzel type, ulna hypoplasia-intellectual disability syndrome, syndactyly-telecanthus-anogenital and renal malformations syndrome, Mononen-Karnes-Senac syndrome, absent radius-anogenital anomalies syndrome, ulnar hypoplasia-split foot syndrome, aphalangy-syndactyly-microcephaly syndrome, 2q37 microdeletion syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, skeletal dysplasia-epilepsy-short stature syndrome, autosomal recessive amelia, temtamy preaxial brachydactyly syndrome, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, acropectoral syndrome, familial digital arthropathy-brachydactyly, Duane-radial ray syndrome, ulnar/fibula ray defect-brachydactyly syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, Al-Gazali syndrome, cocoon syndrome, mammary-digital-nail syndrome, syndactyly-camptodactyly and clinodactyly of fifth fingers-bifid toes syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, split-foot malformation-mesoaxial polydactyly syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, arthrogryposis syndrome, radial deficiency-tibial hypoplasia syndrome, camptodactyly-taurinuria syndrome, fibular dimelia-diplopodia syndrome, shoulder and thorax deformity-congenital heart disease syndrome, Cornelia de Lange syndrome, familial clubfoot with or without associated lower limb anomalies, heart-hand syndrome, hyperphosphatasia-intellectual disability syndrome, limb transversal defect-cardiac anomaly syndrome, triphalangeal thumb-polysyndactyly syndrome, multiple synostoses syndrome, hereditary thrombocytosis with transverse limb defect, thalidomide embryopathy, tibial aplasia-ectrodactyly syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, acrofacial dysostosis, caudal regression-sirenomelia spectrum, Rubinstein-Taybi syndrome, acrocephalosyndactyly, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome

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

6 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
6691	NM_005450.6(NOG):c.665A>G (p.Tyr222Cys)	NOG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6696	NM_005450.6(NOG):c.611G>T (p.Arg204Leu)	NOG	Pathogenic	no assertion criteria provided
6697	NM_005450.6(NOG):c.104C>G (p.Pro35Arg)	NOG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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	tarsal-carpal coalition syndrome	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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOG	HGNC:7866	ENSG00000183691	Q13253	Noggin	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOG	Other/Unknown	no		Noggin, Cystine-knot_cytokine

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOG	2,338

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOG	Q13253	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of cardiac epithelial to mesenchymal transition	1	16852.0×	0.002	NOG
positive regulation of glomerulus development	1	8426.0×	0.002	NOG
neural plate morphogenesis	1	5617.3×	0.002	NOG
cell differentiation in hindbrain	1	5617.3×	0.002	NOG
neural plate anterior/posterior regionalization	1	5617.3×	0.002	NOG
short-term synaptic potentiation	1	5617.3×	0.002	NOG
prostatic bud formation	1	4213.0×	0.002	NOG
axial mesoderm development	1	3370.4×	0.002	NOG
notochord morphogenesis	1	3370.4×	0.002	NOG
ventricular compact myocardium morphogenesis	1	2407.4×	0.002	NOG
regulation of fibroblast growth factor receptor signaling pathway	1	2407.4×	0.002	NOG
atrial cardiac muscle tissue morphogenesis	1	2407.4×	0.002	NOG
ureteric bud formation	1	2407.4×	0.002	NOG
negative regulation of cartilage development	1	2106.5×	0.002	NOG
negative regulation of cardiac muscle cell proliferation	1	1872.4×	0.002	NOG
heart trabecula morphogenesis	1	1872.4×	0.002	NOG
membranous septum morphogenesis	1	1685.2×	0.002	NOG
pharyngeal arch artery morphogenesis	1	1685.2×	0.002	NOG
negative regulation of astrocyte differentiation	1	1532.0×	0.002	NOG
embryonic skeletal joint morphogenesis	1	1532.0×	0.002	NOG
endoderm formation	1	1404.3×	0.002	NOG
endocardial cushion formation	1	1404.3×	0.002	NOG
nodal signaling pathway	1	1123.5×	0.003	NOG
somite development	1	1123.5×	0.003	NOG
lung morphogenesis	1	1053.2×	0.003	NOG
cranial skeletal system development	1	936.2×	0.003	NOG
positive regulation of branching involved in ureteric bud morphogenesis	1	802.5×	0.003	NOG
motor neuron axon guidance	1	702.2×	0.003	NOG
middle ear morphogenesis	1	702.2×	0.003	NOG
regulation of neuronal synaptic plasticity	1	674.1×	0.003	NOG

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	NOG

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)
NOG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04671407	PHASE2	UNKNOWN	The Aim of This Study is to Compare the Efficacy of Perioperative Hypertonic Saline 3% Versus Normal Saline (0.9%) in Decreasing Recurrence Risk in Non-muscle Invasive Bladder Cancer
NCT04147182	PHASE1	UNKNOWN	Perioperative Intravesical Instilation of Hypertonic Saline Following Bladder Tumor Resection

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	1