Thiel-Behnke corneal dystrophy

Summary

Thiel-Behnke corneal dystrophy (MONDO:0011185) is a disease caused by TGFBI (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: TGFBI (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 10
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		173	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0007881	Central corneal dystrophy	Very frequent (80-99%)
HP:0007924	Slow decrease in visual acuity	Very frequent (80-99%)
HP:0008039	Subepithelial corneal opacities	Very frequent (80-99%)
HP:0000495	Recurrent corneal erosions	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0007759	Opacification of the corneal stroma	Frequent (30-79%)
HP:0032148	Episodic pain	Frequent (30-79%)
HP:0200026	Ocular pain	Frequent (30-79%)
HP:0000483	Astigmatism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Thiel-Behnke corneal dystrophy
Mondo ID	MONDO:0011185
MeSH	C535942
OMIM	602082
Orphanet	98960
DOID	DOID:0060455
ICD-11	2082568100
SNOMED CT	417065002
UMLS	C1562894
MedGen	287070
GARD	0009275
Is cancer (heuristic)	no

Also known as: anterior limiting membrane dystrophy type 2 · anterior limiting membrane dystrophy type II · CDB2 · CDTB · corneal dystrophy honeycomb shaped · corneal dystrophy of Bowman layer type 2 · corneal dystrophy of Bowman layer type II · corneal dystrophy of the Bowman layer type 2 · corneal dystrophy Thiel Behnke type · corneal dystrophy, Thiel-Behnke type · curly fiber corneal dystrophy · curly fibre corneal dystrophy · honeycomb corneal dystrophy · TBCD · Thiel Behnke corneal dystrophy · Thiel-Behnke corneal dystrophy · Waardenburg-Jonker corneal dystrophy

Data availability: 10 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 › epithelial-stromal TGFBI dystrophy › Thiel-Behnke corneal dystrophy

Related subtypes (7): corneal granular dystrophy, epithelial basement membrane dystrophy, granular corneal dystrophy type I, lattice corneal dystrophy type I, granular corneal dystrophy type II, Reis-Bucklers corneal dystrophy, corneal dystrophy, lattice type 3A

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

10 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 3 conflicting classifications of pathogenicity, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
7866	NM_000358.3(TGFBI):c.1663C>T (p.Arg555Trp)	TGFBI	Pathogenic	criteria provided, multiple submitters, no conflicts
7867	NM_000358.3(TGFBI):c.1664G>A (p.Arg555Gln)	TGFBI	Pathogenic	criteria provided, multiple submitters, no conflicts
7871	NM_000358.3(TGFBI):c.1501C>A (p.Pro501Thr)	TGFBI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984425	NM_000358.3(TGFBI):c.1772C>A (p.Ser591Tyr)	TGFBI	Likely pathogenic	criteria provided, single submitter
587405	NM_005993.5(TBCD):c.3126G>A (p.Pro1042=)	TBCD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7878	NM_000358.3(TGFBI):c.1998G>C (p.Arg666Ser)	TGFBI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904412	NM_000358.3(TGFBI):c.895G>A (p.Asp299Asn)	TGFBI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587404	NM_005993.5(TBCD):c.2137C>G (p.His713Asp)	TBCD	Uncertain significance	criteria provided, single submitter
4533224	NM_000358.3(TGFBI):c.459+6A>G	TGFBI	Uncertain significance	criteria provided, single submitter
906736	NM_000358.3(TGFBI):c.387G>C (p.Arg129Ser)	TGFBI	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
TGFBI	Definitive	Autosomal dominant	epithelial-stromal TGFBI dystrophy	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGFBI	Orphanet:98956	Epithelial basement membrane dystrophy
TGFBI	Orphanet:98960	Thiel-Behnke corneal dystrophy
TGFBI	Orphanet:98961	Reis-Bücklers corneal dystrophy
TGFBI	Orphanet:98962	Granular corneal dystrophy type I
TGFBI	Orphanet:98963	Granular corneal dystrophy type II
TGFBI	Orphanet:98964	Lattice corneal dystrophy type I
TBCD	Orphanet:496641	Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy 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
TGFBI	HGNC:11771	ENSG00000120708	Q15582	Transforming growth factor-beta-induced protein ig-h3	gencc,clinvar
TBCD	HGNC:11581	ENSG00000141556	Q9BTW9	Tubulin-specific chaperone D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGFBI	Transforming growth factor-beta-induced protein ig-h3	Plays a role in cell adhesion.
TBCD	Tubulin-specific chaperone D	Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly.

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)
TGFBI	Other/Unknown	no		FAS1_domain, EMI_domain, TGFBI/POSTN
TBCD	Other/Unknown	no		ARM-like, ARM-type_fold, TBCD_C

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
amniotic fluid	1
pericardium	1
synovial joint	1
apex of heart	1
right hemisphere of cerebellum	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGFBI	278	ubiquitous	marker	amniotic fluid, synovial joint, pericardium
TBCD	165	ubiquitous	marker	right lobe of thyroid gland, apex of heart, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGFBI	2,988
TBCD	2,066

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBI	Q15582	10
TBCD	Q9BTW9	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Post-chaperonin tubulin folding pathway	1	237.9×	0.010	TBCD
Protein folding	1	129.8×	0.010	TBCD
Metabolism of proteins	2	12.4×	0.010	TGFBI, TBCD
Amyloid fiber formation	1	51.4×	0.019	TGFBI

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
post-chaperonin tubulin folding pathway	1	1404.3×	0.005	TBCD
tubulin complex assembly	1	842.6×	0.005	TBCD
cell morphogenesis involved in neuron differentiation	1	766.0×	0.005	TBCD
negative regulation of microtubule polymerization	1	648.1×	0.005	TBCD
adherens junction assembly	1	648.1×	0.005	TBCD
negative regulation of cell-substrate adhesion	1	526.6×	0.005	TBCD
negative regulation of cell adhesion	1	191.5×	0.013	TGFBI
bicellular tight junction assembly	1	165.2×	0.013	TBCD
chondrocyte differentiation	1	150.5×	0.013	TGFBI
mitotic cell cycle	1	66.9×	0.023	TBCD
extracellular matrix organization	1	61.1×	0.023	TGFBI
microtubule cytoskeleton organization	1	60.6×	0.023	TBCD
protein folding	1	51.7×	0.024	TBCD
cell population proliferation	1	51.4×	0.024	TGFBI
visual perception	1	39.8×	0.028	TGFBI
angiogenesis	1	31.2×	0.034	TGFBI
cell adhesion	1	18.7×	0.053	TGFBI

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBI	0	0
TBCD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TGFBI	1	Binding:1
TBCD	1	Binding:1

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	TGFBI, TBCD

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)
TGFBI	1	—
TBCD	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.