orofaciodigital syndrome IV

Summary

orofaciodigital syndrome IV (MONDO:0009794) is a disease caused by TCTN3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TCTN3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 486
• Phenotypes (HPO): 69

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000157	Abnormality of the tongue	Very frequent (80-99%)
HP:0000161	Median cleft lip	Very frequent (80-99%)
HP:0000168	Abnormality of the gingiva	Very frequent (80-99%)
HP:0000190	Abnormal oral frenulum morphology	Very frequent (80-99%)
HP:0000202	Orofacial cleft	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000356	Abnormality of the outer ear	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000405	Conductive hearing impairment	Very frequent (80-99%)
HP:0000445	Wide nose	Very frequent (80-99%)
HP:0000453	Choanal atresia	Very frequent (80-99%)
HP:0000457	Depressed nasal ridge	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0001162	Postaxial hand polydactyly	Very frequent (80-99%)
HP:0001177	Preaxial hand polydactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001367	Abnormal joint morphology	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001562	Oligohydramnios	Very frequent (80-99%)
HP:0001601	Laryngomalacia	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002970	Genu varum	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0005772	Aplasia/Hypoplasia of the tibia	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0009118	Aplasia/Hypoplasia of the mandible	Very frequent (80-99%)
HP:0010285	Oral synechia	Very frequent (80-99%)
HP:0010469	Absent testis	Very frequent (80-99%)
HP:0010566	Hamartoma	Very frequent (80-99%)
HP:0011267	Microtia, third degree	Very frequent (80-99%)
HP:0011830	Abnormal oral mucosa morphology	Very frequent (80-99%)
HP:0030868	Monorchism	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000176	Submucous cleft hard palate	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0001171	Split hand	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	orofaciodigital syndrome IV
Mondo ID	MONDO:0009794
MeSH	C537133
OMIM	258860
Orphanet	2753
DOID	DOID:0060374
SNOMED CT	239031000
UMLS	C0406727
MedGen	98358
GARD	0000816
Is cancer (heuristic)	no

Also known as: Baraitser-Burn syndrome · Mohr-Majewski syndrome · OFD syndrome 4 · OFD4 · oral facial digital syndrome 4 · oral facial digital syndrome type 4 · oral-facial-digital syndrome type 4 · orofaciodigital syndrome 4 · orofaciodigital syndrome IV · orofaciodigital syndrome type 4 · orofaciodigital syndrome type IV · orofaciodigital syndrome with tibial dysplasia

Data availability: 486 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › orofaciodigital syndrome › orofaciodigital syndrome IV

Related subtypes (18): orofaciodigital syndrome X, orofaciodigital syndrome V, orofaciodigital syndrome type II, orofaciodigital syndrome III, orofaciodigital syndrome IX, orofaciodigital syndrome type 6, orofaciodigital syndrome VIII, orofaciodigital syndrome VII, orofaciodigital syndrome XI, orofaciodigital syndrome type 14, orofaciodigital syndrome XV, orofaciodigital syndrome type 12, orofaciodigital syndrome 16, orofaciodigital syndrome 17, orofaciodigital syndrome 18, orofaciodigital syndrome 19, orofaciodigital syndrome 20, orofaciodigital syndrome 21

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

486 retrieved; paginated sample, class counts are floors:

207 likely benign, 194 uncertain significance, 34 pathogenic, 15 likely pathogenic, 11 pathogenic/likely pathogenic, 9 conflicting classifications of pathogenicity, 8 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1451613	NM_015631.6(TCTN3):c.182dup (p.Gly62fs)	LOC130004408	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217703	NM_015631.6(TCTN3):c.3G>A (p.Met1Ile)	LOC130004408	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2946239	NM_015631.6(TCTN3):c.2T>A (p.Met1Lys)	LOC130004408	Pathogenic	criteria provided, single submitter
1216405	NM_015631.6(TCTN3):c.276_277del (p.Cys92_Asp93delinsTer)	TCTN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1384470	NM_015631.6(TCTN3):c.710del (p.Gly237fs)	TCTN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1393536	NM_015631.6(TCTN3):c.338_341del (p.His113fs)	TCTN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1420657	NM_015631.6(TCTN3):c.940G>T (p.Gly314Ter)	TCTN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1429071	NM_015631.6(TCTN3):c.754del (p.Ser252fs)	TCTN3	Pathogenic	criteria provided, single submitter
1439041	NM_015631.6(TCTN3):c.1520dup (p.Gly508fs)	TCTN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451445	NM_015631.6(TCTN3):c.717_718del (p.Cys239_Ala240insTer)	TCTN3	Pathogenic	criteria provided, single submitter
1451811	NM_015631.6(TCTN3):c.908_911del (p.Leu303fs)	TCTN3	Pathogenic	criteria provided, single submitter
1453812	NM_015631.6(TCTN3):c.2T>G (p.Met1Arg)	TCTN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459264	NM_015631.6(TCTN3):c.650_653del (p.Tyr217fs)	TCTN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1804145	NM_015631.6(TCTN3):c.1A>G (p.Met1Val)	TCTN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2010930	NM_015631.6(TCTN3):c.1226del (p.Gly409fs)	TCTN3	Pathogenic	criteria provided, single submitter
2027808	NM_015631.6(TCTN3):c.910dup (p.Thr304fs)	TCTN3	Pathogenic	criteria provided, multiple submitters, no conflicts
2034806	NM_015631.6(TCTN3):c.2T>C (p.Met1Thr)	TCTN3	Pathogenic	criteria provided, single submitter
208618	NM_015631.6(TCTN3):c.877C>T (p.Gln293Ter)	TCTN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2086552	NM_015631.6(TCTN3):c.920_941del (p.Ala307fs)	TCTN3	Pathogenic	criteria provided, single submitter
2108190	NM_015631.6(TCTN3):c.793dup (p.Ser265fs)	TCTN3	Pathogenic	criteria provided, single submitter
2120440	NM_015631.6(TCTN3):c.1206dup (p.Thr403fs)	TCTN3	Pathogenic	criteria provided, single submitter
2129810	NM_015631.6(TCTN3):c.412_413del (p.Val138fs)	TCTN3	Pathogenic	criteria provided, single submitter
2193739	NM_015631.6(TCTN3):c.1164dup (p.Lys389fs)	TCTN3	Pathogenic	criteria provided, single submitter
2199048	NM_015631.6(TCTN3):c.1068dup (p.Gln357fs)	TCTN3	Pathogenic	criteria provided, single submitter
2201166	NM_015631.6(TCTN3):c.776dup (p.Lys260fs)	TCTN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2413854	NM_015631.6(TCTN3):c.737_738insC (p.Leu248fs)	TCTN3	Pathogenic	criteria provided, single submitter
2927732	NM_015631.6(TCTN3):c.28C>T (p.Gln10Ter)	TCTN3	Pathogenic	criteria provided, single submitter
2946329	NM_015631.6(TCTN3):c.1367_1370dup (p.Glu457fs)	TCTN3	Pathogenic	criteria provided, single submitter
2950265	NM_015631.6(TCTN3):c.371_372del (p.Gly124fs)	TCTN3	Pathogenic	criteria provided, single submitter
2953560	NM_015631.6(TCTN3):c.851dup (p.Val285fs)	TCTN3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
TCTN3	Definitive	Autosomal recessive	orofaciodigital syndrome IV	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCTN3	Orphanet:2753	Orofaciodigital syndrome type 4
TCTN3	Orphanet:2754	Orofaciodigital syndrome type 6
TCTN3	Orphanet:475	Isolated Joubert syndrome
TCTN3	Orphanet:564	Meckel syndrome
ENTPD1	Orphanet:401810	Autosomal recessive spastic paraplegia type 64

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
TCTN3	HGNC:24519	ENSG00000119977	Q6NUS6	Tectonic-3	gencc,clinvar
ENTPD1	HGNC:3363	ENSG00000138185	P49961	Ectonucleoside triphosphate diphosphohydrolase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCTN3	Tectonic-3	Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition.
ENTPD1	Ectonucleoside triphosphate diphosphohydrolase 1	Catalyzes the hydrolysis of nucleoside triphosphates (NTPs) and diphosphates (NDPs).

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCTN3	Other/Unknown	no		TCTN1-3_dom, TCTN1-3, TCTN1-3_N
ENTPD1	Enzyme (other)	yes	3.6.1.5	GDA1_CD39_NTPase

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
corpus epididymis	1
decidua	1
stromal cell of endometrium	1
monocyte	1
mononuclear cell	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCTN3	267	ubiquitous	marker	corpus epididymis, decidua, stromal cell of endometrium
ENTPD1	274	broad	marker	saphenous vein, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ENTPD1	2,623
TCTN3	993

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ENTPD1	P49961	90.85
TCTN3	Q6NUS6	71.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Phosphate bond hydrolysis by NTPDase proteins	1	713.8×	0.007	ENTPD1
Purinergic signaling in leishmaniasis infection	1	211.5×	0.012	ENTPD1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.023	TCTN3
Cilium Assembly	1	54.4×	0.023	TCTN3
Organelle biogenesis and maintenance	1	33.0×	0.030	TCTN3

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
nucleoside diphosphate catabolic process	1	2106.5×	0.003	ENTPD1
ADP catabolic process	1	2106.5×	0.003	ENTPD1
AMP catabolic process	1	1203.7×	0.003	ENTPD1
platelet aggregation	1	168.5×	0.016	ENTPD1
smoothened signaling pathway	1	90.6×	0.021	TCTN3
blood coagulation	1	86.9×	0.021	ENTPD1
cilium assembly	1	36.8×	0.042	TCTN3
positive regulation of apoptotic process	1	28.4×	0.048	TCTN3
cell adhesion	1	18.7×	0.060	ENTPD1
G protein-coupled receptor signaling pathway	1	18.1×	0.060	ENTPD1
apoptotic process	1	14.3×	0.068	TCTN3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ENTPD1	1	3
TCTN3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	ENTPD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ENTPD1	32	Binding:27, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENTPD1	3.6.1.5	apyrase

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)
SURAMIN	3	ENTPD1

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	1	ENTPD1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TCTN3

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)
TCTN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.