Anterior segment dysgenesis 4

Summary

Anterior segment dysgenesis 4 (MONDO:0007662) is a disease caused by PITX2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PITX2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 123

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	anterior segment dysgenesis 4
Mondo ID	MONDO:0007662
OMIM	137600
DOID	DOID:0080609
UMLS	C1842031
MedGen	330750
GARD	0003026
Is cancer (heuristic)	no

Also known as: anterior segment dysgenesis 4 · ASGD4 · IRID2 · iridogoniodysgenesis caused by mutation in PITX2 · iridogoniodysgenesis syndrome · iridogoniodysgenesis type 2 · iridogoniodysgenesis, type 2 · PITX2 iridogoniodysgenesis

Data availability: 123 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 › anterior segment dysgenesis › iridogoniodysgenesis › Rieger anomaly › anterior segment dysgenesis 4

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

123 retrieved; paginated sample, class counts are floors:

49 uncertain significance, 23 pathogenic, 14 conflicting classifications of pathogenicity, 12 benign/likely benign, 11 likely benign, 6 pathogenic/likely pathogenic, 5 likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071052	NM_000325.6(PITX2):c.286C>T (p.Arg96Trp)	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1398374	NM_000325.6(PITX2):c.316G>T (p.Glu106Ter)	PITX2	Pathogenic	criteria provided, single submitter
1449912	NM_000325.6(PITX2):c.522C>G (p.Tyr174Ter)	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455159	NM_000325.6(PITX2):c.700_716dup (p.Thr239_Gly240insCysProGlnGlnTer)	PITX2	Pathogenic	criteria provided, single submitter
1456258	NC_000004.11:g.(?111539281)(111554154_?)del	PITX2	Pathogenic	criteria provided, single submitter
1458040	NM_000325.6(PITX2):c.448_449del (p.Arg150fs)	PITX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1693123	NM_000325.6(PITX2):c.515del (p.Gln172fs)	PITX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1710340	NM_000325.6(PITX2):c.839del (p.Tyr280fs)	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2019449	NM_000325.6(PITX2):c.470_476dup (p.Cys159Ter)	PITX2	Pathogenic	criteria provided, single submitter
2203569	NM_000325.6(PITX2):c.350C>G (p.Pro117Arg)	PITX2	Pathogenic	criteria provided, single submitter
2942566	NM_000325.6(PITX2):c.376G>C (p.Ala126Pro)	PITX2	Pathogenic	criteria provided, single submitter
2950646	NM_000325.6(PITX2):c.250G>T (p.Glu84Ter)	PITX2	Pathogenic	criteria provided, single submitter
3760003	NM_000325.6(PITX2):c.429_430delinsAG (p.Arg144Gly)	PITX2	Pathogenic	criteria provided, single submitter
474011	NM_000325.6(PITX2):c.412-2A>G	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783634	NM_000325.6(PITX2):c.838del (p.Tyr280fs)	PITX2	Pathogenic	criteria provided, single submitter
4785512	NM_000325.6(PITX2):c.256_257insA (p.Pro86fs)	PITX2	Pathogenic	criteria provided, single submitter
4786493	NM_000325.6(PITX2):c.592_604dup (p.Pro202fs)	PITX2	Pathogenic	criteria provided, single submitter
639456	NM_000325.6(PITX2):c.534C>G (p.Tyr178Ter)	PITX2	Pathogenic	criteria provided, single submitter
647394	NM_000325.6(PITX2):c.416G>C (p.Trp139Ser)	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
662470	NM_000325.6(PITX2):c.411+2T>G	PITX2	Pathogenic	criteria provided, single submitter
8086	NM_000325.6(PITX2):c.412-11A>G	PITX2	Pathogenic	criteria provided, multiple submitters, no conflicts
8089	NM_000325.6(PITX2):c.409C>T (p.Arg137Trp)	PITX2	Pathogenic	no assertion criteria provided
8090	NM_000325.6(PITX2):c.365G>A (p.Arg122His)	PITX2	Pathogenic	criteria provided, single submitter
8094	NM_000325.6(PITX2):c.344G>A (p.Arg115His)	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
832808	NC_000004.12:g.(?110618105)(110633018_?)del	PITX2	Pathogenic	criteria provided, single submitter
837823	NM_000325.6(PITX2):c.264del (p.Lys89fs)	PITX2	Pathogenic	criteria provided, single submitter
844916	NM_000325.6(PITX2):c.373del (p.Ile125fs)	PITX2	Pathogenic	criteria provided, single submitter
937285	NM_000325.6(PITX2):c.522_523delinsAA (p.Tyr174_Asp175delinsTer)	PITX2	Pathogenic	criteria provided, single submitter
946640	NM_000325.6(PITX2):c.383G>A (p.Trp128Ter)	PITX2	Pathogenic	criteria provided, single submitter
1066859	NC_000004.11:g.(?111539261)(111543636_?)del	PITX2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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
PITX2	Definitive	Autosomal dominant	anterior segment dysgenesis 4	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PITX2	Orphanet:334	Hereditary atrial fibrillation
PITX2	Orphanet:708	Peters anomaly
PITX2	Orphanet:782	Axenfeld-Rieger syndrome
PITX2	Orphanet:91481	Ring dermoid of cornea
PITX2	Orphanet:91483	Rieger anomaly
PITX2	Orphanet:98978	Axenfeld anomaly

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
PITX2	HGNC:9005	ENSG00000164093	Q99697	Pituitary homeobox 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PITX2	Pituitary homeobox 2	May play a role in myoblast differentiation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PITX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
gingiva	1
gingival epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PITX2	166	broad	marker	gingiva, biceps brachii, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PITX2	2,389

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PITX2	Q99697	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	2855.0×	4e-04	PITX2

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
subthalamic nucleus development	1	16852.0×	7e-04	PITX2
superior vena cava morphogenesis	1	16852.0×	7e-04	PITX2
hypothalamus cell migration	1	8426.0×	7e-04	PITX2
prolactin secreting cell differentiation	1	8426.0×	7e-04	PITX2
left lung morphogenesis	1	8426.0×	7e-04	PITX2
pulmonary vein morphogenesis	1	8426.0×	7e-04	PITX2
cell proliferation involved in outflow tract morphogenesis	1	8426.0×	7e-04	PITX2
pulmonary myocardium development	1	5617.3×	7e-04	PITX2
vascular associated smooth muscle cell differentiation	1	5617.3×	7e-04	PITX2
deltoid tuberosity development	1	5617.3×	7e-04	PITX2
endodermal digestive tract morphogenesis	1	5617.3×	7e-04	PITX2
atrioventricular valve development	1	4213.0×	8e-04	PITX2
somatotropin secreting cell differentiation	1	4213.0×	8e-04	PITX2
extraocular skeletal muscle development	1	2808.7×	1e-03	PITX2
embryonic heart tube left/right pattern formation	1	2808.7×	1e-03	PITX2
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	2407.4×	0.001	PITX2
atrial cardiac muscle tissue morphogenesis	1	2407.4×	0.001	PITX2
hair cell differentiation	1	2106.5×	0.001	PITX2
iris morphogenesis	1	1872.4×	0.001	PITX2
ventricular cardiac muscle cell development	1	1532.0×	0.001	PITX2
embryonic camera-type eye development	1	1203.7×	0.002	PITX2
left/right axis specification	1	1203.7×	0.002	PITX2
embryonic digestive tract morphogenesis	1	936.2×	0.002	PITX2
embryonic hindlimb morphogenesis	1	581.1×	0.003	PITX2
branching involved in blood vessel morphogenesis	1	526.6×	0.003	PITX2
odontogenesis	1	526.6×	0.003	PITX2
ventricular septum morphogenesis	1	432.1×	0.004	PITX2
spleen development	1	401.2×	0.004	PITX2
camera-type eye development	1	358.6×	0.004	PITX2
outflow tract morphogenesis	1	306.4×	0.005	PITX2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
PITX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	PITX2

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)
PITX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.