Oculodentodigital dysplasia

Summary

Oculodentodigital dysplasia (MONDO:0008111) is a disease caused by GJA1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GJA1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 97
• Phenotypes (HPO): 83

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		243	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

83 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000366	Abnormality of the nose	Very frequent (80-99%)
HP:0000430	Underdeveloped nasal alae	Very frequent (80-99%)
HP:0000446	Narrow nasal bridge	Very frequent (80-99%)
HP:0000482	Microcornea	Very frequent (80-99%)
HP:0000598	Abnormality of the ear	Very frequent (80-99%)
HP:0000670	Carious teeth	Very frequent (80-99%)
HP:0000682	Abnormality of dental enamel	Very frequent (80-99%)
HP:0001770	Toe syndactyly	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0006323	Premature loss of primary teeth	Very frequent (80-99%)
HP:0009804	Tooth agenesis	Very frequent (80-99%)
HP:0010761	Broad columella	Very frequent (80-99%)
HP:0000377	Abnormal pinna morphology	Frequent (30-79%)
HP:0000011	Neurogenic bladder	Frequent (30-79%)
HP:0000161	Median cleft lip	Frequent (30-79%)
HP:0000187	Broad alveolar ridges	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000601	Hypotelorism	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000944	Abnormal metaphysis morphology	Frequent (30-79%)
HP:0001231	Abnormal fingernail morphology	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0002212	Curly hair	Frequent (30-79%)
HP:0002217	Slow-growing hair	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0003103	Abnormal cortical bone morphology	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0004437	Cranial hyperostosis	Frequent (30-79%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	oculodentodigital dysplasia
Mondo ID	MONDO:0008111
MeSH	C563160
OMIM	164200
Orphanet	2710
DOID	DOID:0060291
SNOMED CT	38215007
UMLS	C0812437
MedGen	167236
GARD	0007239
MedDRA	10063691
NORD	1519
Is cancer (heuristic)	no

Also known as: Meyer-Schwickerath syndrome · Oculo-Dento-Digital Dysplasia · oculo-dento-digital dysplasia · oculo-dento-digital syndrome · oculodentodigital dysplasia · oculodentodigital syndrome · oculodentoosseous dysplasia · odd syndrome · ODDD · ODDD syndrome

Data availability: 97 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › oculodentodigital dysplasia

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Subtypes (1): oculodentodigital dysplasia, autosomal recessive

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

97 retrieved; paginated sample, class counts are floors:

47 uncertain significance, 16 pathogenic, 15 conflicting classifications of pathogenicity, 7 likely pathogenic, 5 pathogenic/likely pathogenic, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028586	NM_000165.5(GJA1):c.142G>A (p.Glu48Lys)	GJA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16982	NM_000165.5(GJA1):c.50A>C (p.Tyr17Ser)	GJA1	Pathogenic	no assertion criteria provided
16983	NM_000165.5(GJA1):c.52T>C (p.Ser18Pro)	GJA1	Pathogenic	no assertion criteria provided
16984	NM_000165.5(GJA1):c.61G>A (p.Gly21Arg)	GJA1	Pathogenic	criteria provided, single submitter
16985	NM_000165.5(GJA1):c.65G>A (p.Gly22Glu)	GJA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16986	NM_000165.5(GJA1):c.154_156dup (p.Phe52dup)	GJA1	Pathogenic	no assertion criteria provided
16988	NM_000165.5(GJA1):c.286G>A (p.Val96Met)	GJA1	Pathogenic	criteria provided, single submitter
16989	NM_000165.5(GJA1):c.780_781del (p.Cys260fs)	GJA1	Pathogenic	criteria provided, single submitter
16992	NM_000165.5(GJA1):c.581A>C (p.His194Pro)	GJA1	Pathogenic	no assertion criteria provided
16993	NM_000165.5(GJA1):c.32T>C (p.Leu11Pro)	GJA1	Pathogenic	no assertion criteria provided
16994	NM_000165.5(GJA1):c.689_690del (p.Tyr230fs)	GJA1	Pathogenic	no assertion criteria provided
16997	NM_000165.5(GJA1):c.226C>A (p.Arg76Ser)	GJA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2628335	NM_000165.5(GJA1):c.602C>T (p.Ser201Phe)	GJA1	Pathogenic	criteria provided, single submitter
29668	NM_000165.5(GJA1):c.31C>T (p.Leu11Phe)	GJA1	Pathogenic	no assertion criteria provided
435323	NM_000165.5(GJA1):c.119C>T (p.Ala40Val)	GJA1	Pathogenic	criteria provided, multiple submitters, no conflicts
435324	NM_000165.5(GJA1):c.443G>A (p.Arg148Gln)	GJA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435325	NM_000165.5(GJA1):c.646G>T (p.Val216Leu)	GJA1	Pathogenic	criteria provided, single submitter
470216	NM_000165.5(GJA1):c.413G>A (p.Gly138Asp)	GJA1	Pathogenic	criteria provided, multiple submitters, no conflicts
537756	NM_000165.5(GJA1):c.412G>A (p.Gly138Ser)	GJA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88726	NM_000165.5(GJA1):c.617A>G (p.Lys206Arg)	GJA1	Pathogenic	no assertion criteria provided
989202	NM_000165.5(GJA1):c.93T>G (p.Ile31Met)	GJA1	Pathogenic	criteria provided, single submitter
1184546	NM_000165.5(GJA1):c.602C>A (p.Ser201Tyr)	GJA1	Likely pathogenic	no assertion criteria provided
1320166	NM_000165.5(GJA1):c.416T>A (p.Ile139Asn)	GJA1	Likely pathogenic	criteria provided, single submitter
1330230	NM_000165.5(GJA1):c.436_441del (p.Lys146_Met147del)	GJA1	Likely pathogenic	criteria provided, single submitter
3064131	NM_000165.5(GJA1):c.690T>G (p.Tyr230Ter)	GJA1	Likely pathogenic	criteria provided, single submitter
3235928	NM_000165.5(GJA1):c.179G>C (p.Gly60Ala)	GJA1	Likely pathogenic	criteria provided, single submitter
3376584	NM_000165.5(GJA1):c.235G>A (p.Val79Ile)	GJA1	Likely pathogenic	criteria provided, single submitter
4755439	NM_000165.5(GJA1):c.460A>C (p.Thr154Pro)	GJA1	Likely pathogenic	criteria provided, single submitter
16991	NM_000165.5(GJA1):c.1127G>A (p.Arg376Gln)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355156	NM_000165.5(GJA1):c.-135C>T	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 7 · 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
GJA1	Definitive	Autosomal dominant	oculodentodigital dysplasia	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N

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
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
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

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJA1	P17302	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Oligomerization of connexins into connexons	1	3806.7×	1e-03	GJA1
Transport of connexins along the secretory pathway	1	3806.7×	1e-03	GJA1
Regulation of gap junction activity	1	3806.7×	1e-03	GJA1
SARS-CoV-2 targets PDZ proteins in cell-cell junction	1	2284.0×	0.001	GJA1
Formation of annular gap junctions	1	1038.2×	0.002	GJA1
Gap junction degradation	1	951.7×	0.002	GJA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.002	GJA1
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.003	GJA1
Gap junction assembly	1	292.8×	0.004	GJA1
RHOJ GTPase cycle	1	200.3×	0.005	GJA1
RHOQ GTPase cycle	1	181.3×	0.006	GJA1

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
microtubule-based transport	1	16852.0×	9e-04	GJA1
positive regulation of mesodermal cell differentiation	1	16852.0×	9e-04	GJA1
negative regulation of gonadotropin secretion	1	8426.0×	0.001	GJA1
positive regulation of morphogenesis of an epithelium	1	5617.3×	0.001	GJA1
cell communication by electrical coupling	1	4213.0×	0.001	GJA1
negative regulation of trophoblast cell migration	1	2407.4×	0.002	GJA1
gap junction assembly	1	2106.5×	0.002	GJA1
glutamate secretion	1	1685.2×	0.002	GJA1
atrial cardiac muscle cell action potential	1	1685.2×	0.002	GJA1
export across plasma membrane	1	1685.2×	0.002	GJA1
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.002	GJA1
cardiac conduction system development	1	1053.2×	0.002	GJA1
bone remodeling	1	936.2×	0.002	GJA1
xenobiotic transport	1	842.6×	0.003	GJA1
positive regulation of stem cell proliferation	1	526.6×	0.004	GJA1
establishment of mitotic spindle orientation	1	481.5×	0.004	GJA1
maintenance of blood-brain barrier	1	481.5×	0.004	GJA1
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.004	GJA1
cellular response to amyloid-beta	1	391.9×	0.004	GJA1
bone development	1	276.3×	0.005	GJA1
monoatomic ion transmembrane transport	1	208.1×	0.007	GJA1
positive regulation of cold-induced thermogenesis	1	163.6×	0.008	GJA1
negative regulation of cell growth	1	144.0×	0.009	GJA1
intracellular protein localization	1	104.7×	0.012	GJA1
heart development	1	78.8×	0.015	GJA1
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	GJA1
cell-cell signaling	1	69.6×	0.016	GJA1
positive regulation of gene expression	1	38.7×	0.028	GJA1
spermatogenesis	1	35.2×	0.029	GJA1
signal transduction	1	16.1×	0.062	GJA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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: 1; 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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.