orofaciodigital syndrome IX

Summary

orofaciodigital syndrome IX (MONDO:0009795) is a disease caused by TBC1D32 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TBC1D32 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 11

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

Identifiers

Disease identifiers

Field	Value
Canonical name	orofaciodigital syndrome IX
Mondo ID	MONDO:0009795
MeSH	C557818
OMIM	258865
Orphanet	141007
DOID	DOID:0060382
SNOMED CT	718680001
UMLS	C0796102
MedGen	162908
GARD	0010520
Is cancer (heuristic)	no

Also known as: OFD syndrome 9 · OFD9 · oral facial digital syndrome 9 · oral facial digital syndrome type 9 · oral-facial-digital syndrome type 9 · oral-facial-digital syndrome with retinal abnormalities · orofaciodigital syndrome 9 · orofaciodigital syndrome IX · orofaciodigital syndrome type IX · orofaciodigital syndrome with retinal abnormalities

Data availability: 11 ClinVar variants · 2 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 IX

Related subtypes (18): orofaciodigital syndrome X, orofaciodigital syndrome V, orofaciodigital syndrome type II, orofaciodigital syndrome III, orofaciodigital syndrome IV, 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

11 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500743	NM_152730.6(TBC1D32):c.2200C>T (p.Arg734Ter)	TBC1D32	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4075386	NM_152730.6(TBC1D32):c.2151del (p.Lys717fs)	TBC1D32	Pathogenic	no assertion criteria provided
4075388	R734*	TBC1D32	Pathogenic	no assertion criteria provided
4075389	TBC1D32, IVS, G-T, -1	TBC1D32	Pathogenic	no assertion criteria provided
4075390	TBC1D32, 1-BP DEL, NT2073	TBC1D32	Pathogenic	no assertion criteria provided
4075391	TBC1D32, IVS6, G-A, +5	TBC1D32	Pathogenic	no assertion criteria provided
139613	NM_152730.6(TBC1D32):c.1372+1G>T	TBC1D32	Likely pathogenic	criteria provided, single submitter
4279038	NM_152730.6(TBC1D32):c.1774dup (p.Leu592fs)	TBC1D32	Likely pathogenic	criteria provided, single submitter
3062022	NM_152730.6(TBC1D32):c.769+5G>A	TBC1D32	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
599231	NM_144643.4(SCLT1):c.1294-1_1294dup	SCLT1	Uncertain significance	no assertion criteria provided
3898248	NM_152730.6(TBC1D32):c.1165_1166dup (p.Gln390fs)	TBC1D32	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
TBC1D32	Strong	Autosomal recessive	orofaciodigital syndrome IX	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBC1D32	Orphanet:141007	Orofaciodigital syndrome type 9
SCLT1	Orphanet:110	Bardet-Biedl 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
TBC1D32	HGNC:21485	ENSG00000146350	Q96NH3	Protein broad-minded	gencc,clinvar
SCLT1	HGNC:26406	ENSG00000151466	Q96NL6	Sodium channel and clathrin linker 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBC1D32	Protein broad-minded	Required for high-level Shh responses in the developing neural tube.
SCLT1	Sodium channel and clathrin linker 1	Adapter protein that links SCN10A to clathrin.

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)
TBC1D32	Other/Unknown	no		BROMI_M, Rab-GAP_TBC_sf, PHAF1/BROMI
SCLT1	Other/Unknown	no		SCLT1

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
buccal mucosa cell	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBC1D32	208	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
SCLT1	217	ubiquitous	marker	buccal mucosa cell, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCLT1	1,478
TBC1D32	919

Intra-cohort edges

A	B	Sources
SCLT1	TBC1D32	string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCLT1	Q96NL6	82.44
TBC1D32	Q96NH3	80.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Anchoring of the basal body to the plasma membrane	1	113.1×	0.014	SCLT1
Cilium Assembly	1	108.8×	0.014	SCLT1
Organelle biogenesis and maintenance	1	66.0×	0.015	SCLT1

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
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	2106.5×	0.005	TBC1D32
clustering of voltage-gated sodium channels	1	1203.7×	0.005	SCLT1
retinal pigment epithelium development	1	842.6×	0.005	TBC1D32
protein localization to cilium	1	200.6×	0.011	TBC1D32
lens development in camera-type eye	1	187.2×	0.011	TBC1D32
embryonic digit morphogenesis	1	150.5×	0.011	TBC1D32
non-motile cilium assembly	1	145.3×	0.011	TBC1D32
determination of left/right symmetry	1	127.7×	0.011	TBC1D32
roof of mouth development	1	123.9×	0.011	TBC1D32
kidney development	1	70.2×	0.017	TBC1D32
heart development	1	39.4×	0.027	TBC1D32
cilium assembly	1	36.8×	0.027	SCLT1

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
TBC1D32	0	0
SCLT1	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	TBC1D32, SCLT1

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)
TBC1D32	0	—
SCLT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.