Anterior segment dysgenesis 1

Summary

Anterior segment dysgenesis 1 (MONDO:0007138) is a disease caused by variants in PITX3 and FOXE3, with 3 cohort genes and 1 clinical trial.

At a glance

• Causal genes: PITX3 (GenCC Definitive), FOXE3 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 6
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	anterior segment dysgenesis 1
Mondo ID	MONDO:0007138
OMIM	107250
DOID	DOID:0060605, DOID:0080606
UMLS	C4551992
MedGen	1631197
GARD	0024525
Is cancer (heuristic)	no

Also known as: anterior segment dysgenesis 1 · anterior segment dysgenesis 1, multiple subtypes · anterior segment mesenchymal dysgenesis · ASGD1 · ASMD

Data availability: 6 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › anterior segment dysgenesis › anterior segment dysgenesis 1

Related subtypes (7): anterior segment dysgenesis 7, iridogoniodysgenesis, Peters anomaly, congenital primary aphakia, anterior segment dysgenesis 6, anterior segment dysgenesis 8, isolated iridoschisis

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 uncertain significance, 2 benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
468353	NM_005029.4(PITX3):c.640_656dup (p.Gly220fs)	GBF1	Pathogenic	criteria provided, multiple submitters, no conflicts
468252	NM_005029.4(PITX3):c.640_656del (p.Ala214fs)	PITX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
655743	NM_012186.3(FOXE3):c.575CGCCCG[1] (p.192AP[1])	FOXE3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301674	NM_005029.4(PITX3):c.88G>A (p.Glu30Lys)	GBF1	Uncertain significance	criteria provided, single submitter
501413	NM_012186.3(FOXE3):c.146G>C (p.Gly49Ala)	FOXE3	Benign	criteria provided, multiple submitters, no conflicts
196404	NM_005029.4(PITX3):c.285C>T (p.Ile95=)	GBF1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · 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
PITX3	Definitive	Autosomal dominant	anterior segment dysgenesis 1	7
FOXE3	Strong	Autosomal dominant	anterior segment dysgenesis 1	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXE3	Orphanet:708	Peters anomaly
FOXE3	Orphanet:83461	Congenital primary aphakia
FOXE3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
PITX3	Orphanet:162	Congenital cataract-anterior segment dysgenesis syndrome
PITX3	Orphanet:98993	Early-onset posterior polar cataract

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXE3	HGNC:3808	ENSG00000186790	Q13461	Forkhead box protein E3	gencc,clinvar
PITX3	HGNC:9006	ENSG00000107859	O75364	Pituitary homeobox 3	gencc,clinvar
GBF1	HGNC:4181	ENSG00000107862	Q92538	Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXE3	Forkhead box protein E3	Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle.
PITX3	Pituitary homeobox 3	Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development.
GBF1	Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1	Guanine-nucleotide exchange factor (GEF) for members of the Arf family of small GTPases involved in trafficking in the early secretory pathway; its GEF activity initiates the coating of nascent vesicles via the localized generation of acti…

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Transcription factor	2	5.5×	0.081
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXE3	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
PITX3	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
GBF1	Other/Unknown	no		Sec7_dom, ARM-type_fold, Sec7_C_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
hindlimb stylopod muscle	1
triceps brachii	1
adenohypophysis	1
colonic epithelium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXE3	36	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon
PITX3	64	tissue_specific	yes	hindlimb stylopod muscle, triceps brachii, primordial germ cell in gonad
GBF1	259	ubiquitous	marker	colonic epithelium, ventricular zone, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GBF1	2,436
PITX3	1,186
FOXE3	1,003

Intra-cohort edges

A	B	Sources
FOXE3	PITX3	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GBF1	Q92538	71.42
FOXE3	Q13461	66.68
PITX3	O75364	63.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 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
Assembly and Release of Dengue Virus Virions	1	1427.5×	0.004	GBF1
VxPx cargo-targeting to cilium	1	519.1×	0.006	GBF1
trans-Golgi Network Vesicle Budding	1	253.8×	0.008	GBF1
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.011	GBF1
COPI-mediated anterograde transport	1	109.8×	0.011	GBF1
Dengue Virus-Host Interactions	1	45.7×	0.022	GBF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lens development in camera-type eye	2	249.7×	0.001	FOXE3, PITX3
cell activation involved in immune response	1	5617.3×	0.002	GBF1
protein localization to endoplasmic reticulum tubular network	1	5617.3×	0.002	GBF1
trabecular meshwork development	1	2808.7×	0.002	FOXE3
negative regulation of gliogenesis	1	2808.7×	0.002	PITX3
establishment of monopolar cell polarity	1	2808.7×	0.002	GBF1
endoplasmic reticulum-Golgi intermediate compartment organization	1	2808.7×	0.002	GBF1
response to methamphetamine hydrochloride	1	2808.7×	0.002	PITX3
positive regulation of cell proliferation in midbrain	1	2808.7×	0.002	PITX3
cellular response to glial cell derived neurotrophic factor	1	2808.7×	0.002	PITX3
positive regulation of lens epithelial cell proliferation	1	2808.7×	0.002	FOXE3
anatomical structure morphogenesis	2	92.8×	0.002	FOXE3, PITX3
ciliary body morphogenesis	1	1404.3×	0.003	FOXE3
Golgi disassembly	1	936.2×	0.004	GBF1
negative regulation of lens fiber cell differentiation	1	936.2×	0.004	FOXE3
COPI coating of Golgi vesicle	1	802.5×	0.004	GBF1
protein localization to endoplasmic reticulum exit site	1	702.2×	0.005	GBF1
iris morphogenesis	1	624.1×	0.005	FOXE3
reactive oxygen species biosynthetic process	1	624.1×	0.005	GBF1
regulation of protein localization to cell surface	1	561.7×	0.005	GBF1
lens morphogenesis in camera-type eye	1	432.1×	0.006	PITX3
cornea development in camera-type eye	1	432.1×	0.006	FOXE3
post-Golgi vesicle-mediated transport	1	351.1×	0.006	GBF1
Golgi to endosome transport	1	351.1×	0.006	GBF1
lens fiber cell differentiation	1	351.1×	0.006	PITX3
regulation of ARF protein signal transduction	1	295.6×	0.007	GBF1
cell development	1	295.6×	0.007	FOXE3
protein localization to Golgi apparatus	1	267.5×	0.007	GBF1
response to immobilization stress	1	244.2×	0.008	PITX3
dopaminergic neuron differentiation	1	208.1×	0.009	PITX3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
FOXE3	0	0
PITX3	0	0
GBF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	FOXE3, PITX3, GBF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXE3	0	—
PITX3	0	—
GBF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05641103	Not specified	COMPLETED	PREDIGA 2: Spanish Acronym of Educational and Diagnostic Project for Gaucher and ASMD