Peters anomaly

Summary

Peters anomaly (MONDO:0011414) is a disease caused by PAX6 (GenCC Definitive), with 21 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PAX6 (GenCC Definitive)
• Cohort genes: 21
• ClinVar variants: 673
• Phenotypes (HPO): 9
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000659	Peters anomaly	Obligate (100%)
HP:0000523	Subcapsular cataract	Very frequent (80-99%)
HP:0007759	Opacification of the corneal stroma	Very frequent (80-99%)
HP:0011483	Anterior synechiae of the anterior chamber	Very frequent (80-99%)
HP:0011493	Central opacification of the cornea	Very frequent (80-99%)
HP:0031159	Thinning of Descemet membrane	Very frequent (80-99%)
HP:0001087	Developmental glaucoma	Frequent (30-79%)
HP:0000486	Strabismus	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Peters anomaly
Mondo ID	MONDO:0011414
MeSH	C537884
OMIM	604229
Orphanet	708
DOID	DOID:0060673, DOID:0080610
ICD-11	1902926622
SNOMED CT	204153003
UMLS	C0344559
MedGen	91031
GARD	0007377
MedDRA	10059202
Is cancer (heuristic)	no

Also known as: anterior segment dysgenesis 5, multiple subtypes · ASGD5 · Peters anomaly · Peters anomaly (disease) · Peters congenital glaucoma

Data availability: 673 ClinVar variants · 7 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › corneal disorder › Peters anomaly

Related subtypes (23): cornea plana, pseudopterygium, corneal deposit, Bowman’s membrane folds or rupture, corneal degeneration, corneal staphyloma, corneal argyrosis, corneal ectasia, keratopathy, keratitis, corneal edema, brittle cornea syndrome, megalocornea, X-linked corneal dermoid, pellucid marginal degeneration, keratoconus, corneal dystrophy, sclerocornea, cornea neoplasm, Arnold stickler bourne syndrome, limbal stem cell deficiency, thygeson superficial punctate keratopathy, Terrien marginal degeneration

Subtypes (2): Peters anomaly-cataract syndrome, von Hippel anomaly

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

600 retrieved; paginated sample, class counts are floors:

187 uncertain significance, 154 pathogenic, 144 likely benign, 46 conflicting classifications of pathogenicity, 22 benign, 21 likely pathogenic, 18 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1727216	NM_004491.5(ARHGAP35):c.4444del (p.Gln1482fs)	ARHGAP35	Pathogenic	criteria provided, single submitter
2628039	NM_001845.6(COL4A1):c.388G>T (p.Gly130Trp)	COL4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
417858	NM_000104.4(CYP1B1):c.1063_1075del (p.Arg355fs)	CYP1B1	Pathogenic	no assertion criteria provided
68466	NM_000104.4(CYP1B1):c.1200_1209dup (p.Thr404fs)	CYP1B1	Pathogenic	reviewed by expert panel
7737	NM_000104.4(CYP1B1):c.171G>A (p.Trp57Ter)	CYP1B1	Pathogenic	reviewed by expert panel
1072681	NC_000011.9:g.(?31284590)(31824402_?)del	DNAJC24	Pathogenic	criteria provided, single submitter
647471	NC_000011.9:g.(?31284590)(31832374_?)del	DNAJC24	Pathogenic	criteria provided, single submitter
1458968	NC_000011.9:g.(?31804921)(31812428_?)del	ELP4	Pathogenic	criteria provided, single submitter
2422793	NC_000011.9:g.(?31625295)(31822424_?)del	ELP4	Pathogenic	criteria provided, single submitter
2422796	NC_000011.9:g.(?31804921)(31816356_?)del	ELP4	Pathogenic	criteria provided, single submitter
3474	NM_001368894.2(PAX6):c.1310A>T (p.Ter437Leu)	ELP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372441	NM_001368894.2(PAX6):c.664C>T (p.Arg222Trp)	ELP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
529895	NC_000011.10:g.(?31789934)(31806411_?)del	ELP4	Pathogenic	criteria provided, single submitter
583750	NC_000011.9:g.(?31284590)(32456911_?)del	ELP4	Pathogenic	criteria provided, single submitter
584225	NC_000011.10:g.(?31664397)(31794829_?)del	ELP4-AS1	Pathogenic	criteria provided, single submitter
8448	NM_012186.3(FOXE3):c.720C>A (p.Cys240Ter)	FOXE3	Pathogenic	criteria provided, multiple submitters, no conflicts
1023138	NM_001368894.2(PAX6):c.275T>A (p.Val92Glu)	PAX6	Pathogenic	criteria provided, multiple submitters, no conflicts
1069925	NM_001368894.2(PAX6):c.790_806del (p.Pro264fs)	PAX6	Pathogenic	criteria provided, single submitter
1070548	NM_001368894.2(PAX6):c.483del (p.Met162fs)	PAX6	Pathogenic	criteria provided, single submitter
1072682	NC_000011.9:g.(?31804921)(31816377_?)del	PAX6	Pathogenic	criteria provided, single submitter
1075087	NM_001368894.2(PAX6):c.720del (p.Glu242fs)	PAX6	Pathogenic	criteria provided, single submitter
1075401	NM_001368894.2(PAX6):c.52G>A (p.Gly18Arg)	PAX6	Pathogenic	criteria provided, single submitter
1254586	NM_001368894.2(PAX6):c.1090C>T (p.Gln364Ter)	PAX6	Pathogenic	criteria provided, multiple submitters, no conflicts
1372939	NM_001368894.2(PAX6):c.829del (p.Ala277fs)	PAX6	Pathogenic	criteria provided, single submitter
1389199	NM_001368894.2(PAX6):c.1061del (p.Asn354fs)	PAX6	Pathogenic	criteria provided, single submitter
1390086	NM_001368894.2(PAX6):c.1086del (p.Ser363fs)	PAX6	Pathogenic	criteria provided, single submitter
1429880	NM_001368894.2(PAX6):c.385_386dup (p.Asp129fs)	PAX6	Pathogenic	criteria provided, single submitter
1434624	NM_001368894.2(PAX6):c.399+2T>C	PAX6	Pathogenic	criteria provided, single submitter
1434660	NM_001368894.2(PAX6):c.1074+1G>C	PAX6	Pathogenic	criteria provided, multiple submitters, no conflicts
1451194	NM_001368894.2(PAX6):c.709G>T (p.Glu237Ter)	PAX6	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 59 · Orphanet: 60 · 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
PAX6	Definitive	Autosomal dominant	Peters anomaly	14
CYP1B1	Supportive	Autosomal dominant	Peters anomaly	6
FOXC1	Supportive	Autosomal dominant	Peters anomaly	10
FOXE3	Supportive	Autosomal dominant	Peters anomaly	14
PITX2	Supportive	Autosomal dominant	Rieger anomaly	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP1B1	Orphanet:708	Peters anomaly
CYP1B1	Orphanet:98976	Congenital glaucoma
CYP1B1	Orphanet:98977	Juvenile glaucoma
FOXE3	Orphanet:708	Peters anomaly
FOXE3	Orphanet:83461	Congenital primary aphakia
FOXE3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
PAX6	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
PAX6	Orphanet:2253	Foveal hypoplasia-presenile cataract syndrome
PAX6	Orphanet:2334	Autosomal dominant keratitis
PAX6	Orphanet:250923	Isolated aniridia
PAX6	Orphanet:35737	Morning glory disc anomaly
PAX6	Orphanet:708	Peters anomaly
PAX6	Orphanet:893	WAGR syndrome
PAX6	Orphanet:98942	Coloboma of choroid and retina
PAX6	Orphanet:98943	Coloboma of eye lens
PAX6	Orphanet:98944	Coloboma of iris
PAX6	Orphanet:98945	Coloboma of macula
PAX6	Orphanet:98946	Coloboma of eyelid
PAX6	Orphanet:98947	Coloboma of optic disc
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
FOXC1	Orphanet:250923	Isolated aniridia
FOXC1	Orphanet:708	Peters anomaly
FOXC1	Orphanet:782	Axenfeld-Rieger syndrome
FOXC1	Orphanet:91483	Rieger anomaly
FOXC1	Orphanet:98978	Axenfeld anomaly
BMP4	Orphanet:139471	Microphthalmia with brain and digit anomalies
BMP4	Orphanet:199306	Cleft lip/palate
BMP4	Orphanet:828	Stickler syndrome
BMP4	Orphanet:93100	Renal agenesis, unilateral
PRPF8	Orphanet:528084	Non-specific syndromic intellectual disability
PRPF8	Orphanet:791	Retinitis pigmentosa
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly
FAT4	Orphanet:2136	Hennekam syndrome
FAT4	Orphanet:314679	Cerebrofacioarticular syndrome
FREM1	Orphanet:217266	BNAR syndrome
FREM1	Orphanet:2717	Oculotrichoanal syndrome
FREM1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FREM1	Orphanet:93100	Renal agenesis, unilateral
DAB1	Orphanet:363710	Spinocerebellar ataxia type 37

Cohort genes → proteins

21 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	21

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP1B1	HGNC:2597	ENSG00000138061	Q16678	Cytochrome P450 1B1	gencc,clinvar
FOXE3	HGNC:3808	ENSG00000186790	Q13461	Forkhead box protein E3	gencc,clinvar
PAX6	HGNC:8620	ENSG00000007372	P26367	Paired box protein Pax-6	gencc,clinvar
PITX2	HGNC:9005	ENSG00000164093	Q99697	Pituitary homeobox 2	gencc,clinvar
FOXC1	HGNC:3800	ENSG00000054598	Q12948	Forkhead box protein C1	gencc
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	clinvar
ELP4	HGNC:1171	ENSG00000109911	Q96EB1	Elongator complex protein 4	clinvar
PRPF8	HGNC:17340	ENSG00000174231	Q6P2Q9	Pre-mRNA-processing-splicing factor 8	clinvar
PITRM1	HGNC:17663	ENSG00000107959	Q5JRX3	Presequence protease, mitochondrial	clinvar
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	clinvar
FAT4	HGNC:23109	ENSG00000196159	Q6V0I7	Protocadherin Fat 4	clinvar
FREM1	HGNC:23399	ENSG00000164946	Q5H8C1	FRAS1-related extracellular matrix protein 1	clinvar
DAB1	HGNC:2661	ENSG00000173406	O75553	Disabled homolog 1	clinvar
DNAJC24	HGNC:26979	ENSG00000170946	Q6P3W2	DnaJ homolog subfamily C member 24	clinvar
EPHB2	HGNC:3393	ENSG00000133216	P29323	Ephrin type-B receptor 2	clinvar
FAT1	HGNC:3595	ENSG00000083857	Q14517	Protocadherin Fat 1	clinvar
PITRM1-AS1	HGNC:44675	ENSG00000237399		PITRM1 antisense RNA 1	clinvar
ARHGAP35	HGNC:4591	ENSG00000160007	Q9NRY4	Rho GTPase-activating protein 35	clinvar
ELP4-AS1	HGNC:58222	ENSG00000228061		ELP4 antisense RNA 1	clinvar
PTCH1	HGNC:9585	ENSG00000185920	Q13635	Protein patched homolog 1	clinvar
RARG	HGNC:9866	ENSG00000172819	P13631	Retinoic acid receptor gamma	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP1B1	Cytochrome P450 1B1	A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins.
FOXE3	Forkhead box protein E3	Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle.
PAX6	Paired box protein Pax-6	Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas.
PITX2	Pituitary homeobox 2	May play a role in myoblast differentiation.
FOXC1	Forkhead box protein C1	DNA-binding transcriptional factor that plays a role in a broad range of cellular and developmental processes such as eye, bones, cardiovascular, kidney and skin development.
BMP4	Bone morphogenetic protein 4	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis.
ELP4	Elongator complex protein 4	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
PRPF8	Pre-mRNA-processing-splicing factor 8	Plays a role in pre-mRNA splicing as core component of precatalytic, catalytic and postcatalytic spliceosomal complexes, both of the predominant U2-type spliceosome and the minor U12-type spliceosome.
PITRM1	Presequence protease, mitochondrial	Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing.
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
FAT4	Protocadherin Fat 4	Cadherins are calcium-dependent cell adhesion proteins.
FREM1	FRAS1-related extracellular matrix protein 1	Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.
DAB1	Disabled homolog 1	Signaling adapter of the reelin-mediated signaling pathway, which regulates the migration and differentiation of postmitotic neurons during brain development.
DNAJC24	DnaJ homolog subfamily C member 24	Stimulates the ATPase activity of several Hsp70-type chaperones.
EPHB2	Ephrin type-B receptor 2	Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.
FAT1	Protocadherin Fat 1	Plays an essential role for cellular polarization, directed cell migration and modulating cell-cell contact.
ARHGAP35	Rho GTPase-activating protein 35	Rho GTPase-activating protein (GAP).
PTCH1	Protein patched homolog 1	Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH).
RARG	Retinoic acid receptor gamma	Receptor for retinoic acid.

Protein-family classification

Druggable: 3 · Difficult: 4 · Unknown: 14 · Druggable fraction: 0.14

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
Nuclear receptor	1	18.4×	0.265
Transcription factor	4	1.6×	0.408
Other/Unknown	14	1.2×	0.408
Protease	1	1.7×	0.538
Kinase	1	1.3×	0.538

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP1B1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
FOXE3	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
PAX6	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
PITX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
FOXC1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
ELP4	Other/Unknown	no		Elongator_complex_protein_4, P-loop_NTPase
PRPF8	Other/Unknown	no		JAMM/MPN+_dom, RNaseH-like_sf, PRO8NT
PITRM1	Protease	yes	3.4.24.56	Peptidase_M16_C, Metalloenz_LuxS/M16, Pept_M16_N
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
FAT4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
FREM1	Other/Unknown	no		C-type_lectin-like, Calx_beta, C-type_lectin-like/link_sf
DAB1	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, DAB1/2_SBM
DNAJC24	Other/Unknown	no		DnaJ_domain, DPH_MB_dom, DPH_MB_sf
EPHB2	Kinase	yes	2.7.10.1	Prot_kinase_dom, EPH_LBD, Ser-Thr/Tyr_kinase_cat_dom
FAT1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
PITRM1-AS1	Other/Unknown	no
ARHGAP35	Other/Unknown	no		RhoGAP_dom, Small_GTPase, FF_domain
ELP4-AS1	Other/Unknown	no
PTCH1	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD
RARG	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

18 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)	21
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	5
male germ line stem cell (sensu Vertebrata) in testis	3
cortical plate	3
primordial germ cell in gonad	2
trigeminal ganglion	2
calcaneal tendon	2
sural nerve	2
Brodmann (1909) area 23	2
endothelial cell	2
ganglionic eminence	2
tibia	2
cartilage tissue	1
pericardium	1
synovial joint	1
mucosa of transverse colon	1
palpebral conjunctiva	1
type B pancreatic cell	1
biceps brachii	1
gingiva	1
gingival epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP1B1	285	ubiquitous	marker	pericardium, cartilage tissue, synovial joint
FOXE3	36	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon
PAX6	201	broad	marker	palpebral conjunctiva, type B pancreatic cell, ventricular zone
PITX2	166	broad	marker	gingiva, biceps brachii, gingival epithelium
FOXC1	267	ubiquitous	marker	parotid gland, vena cava, trigeminal ganglion
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum
ELP4	250	ubiquitous	marker	ventricular zone, calcaneal tendon, primordial germ cell in gonad
PRPF8	145	ubiquitous	marker	adenohypophysis, pituitary gland, ventricular zone
PITRM1	292	ubiquitous	marker	apex of heart, adrenal tissue, right adrenal gland cortex
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery
FAT4	231	ubiquitous	marker	calcaneal tendon, cortical plate, blood vessel layer
FREM1	171	broad	marker	kidney epithelium, smooth muscle tissue, metanephros
DAB1	190	broad	marker	cortical plate, jejunal mucosa, sural nerve
DNAJC24	288	ubiquitous	marker	heart right ventricle, endothelial cell, Brodmann (1909) area 23
EPHB2	214	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate
FAT1	288	ubiquitous	marker	choroid plexus epithelium, tibia, metanephric glomerulus
PITRM1-AS1	160		yes	male germ line stem cell (sensu Vertebrata) in testis, left ovary, sural nerve
ARHGAP35	277	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
ELP4-AS1	124		yes	ventricular zone, ganglionic eminence, male germ line stem cell (sensu Vertebrata) in testis
PTCH1	275	ubiquitous	marker	tibia, dorsal root ganglion, trigeminal ganglion
RARG	199	ubiquitous	marker	lower esophagus mucosa, skin of leg, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRPF8	5,582
PAX6	4,971
BMP4	4,425
PTCH1	3,368
EPHB2	3,042
COL4A1	2,909
FOXC1	2,896
CYP1B1	2,883
FAT1	2,446
PITX2	2,389

Intra-cohort edges

A	B	Sources
BMP4	FOXC1	string_interaction
BMP4	PITX2	string_interaction
CYP1B1	FOXC1	string_interaction
CYP1B1	PITX2	string_interaction
DNAJC24	ELP4	string_interaction
DNAJC24	PAX6	string_interaction
ELP4	PAX6	string_interaction
FAT1	FAT4	string_interaction
FOXC1	PAX6	string_interaction
FOXC1	PITX2	intact, string_interaction
FOXE3	PAX6	string_interaction
FOXE3	PITX2	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 7 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRPF8	Q6P2Q9	101
PTCH1	Q13635	16
RARG	P13631	11
PITRM1	Q5JRX3	8
ARHGAP35	Q9NRY4	6
EPHB2	P29323	5
COL4A1	P02462	4
PITX2	Q99697	3
CYP1B1	Q16678	2
PAX6	P26367	2
FAT4	Q6V0I7	2
DNAJC24	Q6P3W2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BMP4	P12644	79.12
FREM1	Q5H8C1	75.75
ELP4	Q96EB1	74.49
FOXE3	Q13461	66.68
DAB1	O75553	59.20
FOXC1	Q12948	56.09
FAT1	Q14517

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 80. Enrichment computed across 21 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of intermediate mesoderm	2	190.3×	0.004	BMP4, FOXC1
Formation of the ureteric bud	2	66.2×	0.016	BMP4, FOXC1
Defective CYP1B1 causes Glaucoma	1	761.3×	0.035	CYP1B1
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	190.3×	0.072	PITX2
Formation of lateral plate mesoderm	1	152.3×	0.072	BMP4
Reelin signalling pathway	1	126.9×	0.072	DAB1
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	108.8×	0.072	PTCH1
Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)	1	95.2×	0.072	CYP1B1
Sema4D mediated inhibition of cell attachment and migration	1	95.2×	0.072	ARHGAP35
Synthesis of diphthamide-EEF2	1	95.2×	0.072	DNAJC24
Ligand-receptor interactions	1	95.2×	0.072	PTCH1
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)	1	84.6×	0.072	CYP1B1
Activation of anterior HOX genes in hindbrain development during early embryogenesis	2	12.2×	0.072	PAX6, RARG
Formation of the anterior neural plate	1	69.2×	0.077	PAX6
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	58.6×	0.077	PAX6
Specification of primordial germ cells	1	58.6×	0.077	BMP4
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	54.4×	0.077	ARHGAP35
Kidney development	1	54.4×	0.077	BMP4
Anchoring fibril formation	1	50.8×	0.077	COL4A1
Germ layer formation at gastrulation	1	44.8×	0.077	BMP4
Activation of SMO	1	42.3×	0.077	PTCH1
Formation of the nephric duct	1	42.3×	0.077	BMP4
Specification of the neural plate border	1	42.3×	0.077	BMP4
Scavenging by Class A Receptors	1	40.1×	0.077	COL4A1
Fibronectin matrix formation	1	38.1×	0.077	COL4A1
Crosslinking of collagen fibrils	1	38.1×	0.077	COL4A1
Ephrin signaling	1	38.1×	0.077	EPHB2
Regulation of gene expression in beta cells	1	34.6×	0.079	PAX6
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	34.6×	0.079	PAX6
Attachment of bacteria to epithelial cells	1	33.1×	0.079	COL4A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
iris morphogenesis	3	295.6×	5e-05	FOXE3, PAX6, PITX2
anatomical structure morphogenesis	5	36.6×	5e-05	FOXE3, PITX2, FREM1, FAT1, FOXC1
trabecular meshwork development	2	887.0×	2e-04	CYP1B1, FOXE3
neural tube closure	4	39.4×	3e-04	BMP4, ARHGAP35, PTCH1, RARG
deltoid tuberosity development	2	591.3×	3e-04	PITX2, BMP4
embryonic hindlimb morphogenesis	3	91.8×	3e-04	PITX2, BMP4, RARG
lens development in camera-type eye	3	59.1×	0.001	FOXE3, PAX6, FAT1
camera-type eye development	3	56.6×	0.001	PITX2, FOXC1, ARHGAP35
eye development	3	55.4×	0.001	FOXE3, PAX6, FOXC1
retinal blood vessel morphogenesis	2	253.4×	0.001	CYP1B1, COL4A1
lacrimal gland development	2	221.7×	0.001	PAX6, FOXC1
positive regulation of epidermal cell differentiation	2	221.7×	0.001	BMP4, PTCH1
ventral spinal cord development	2	197.1×	0.002	PAX6, DAB1
collagen fibril organization	3	35.5×	0.003	CYP1B1, COL4A1, FOXC1
negative regulation of axonogenesis	2	136.4×	0.003	DAB1, EPHB2
cornea development in camera-type eye	2	136.4×	0.003	FOXE3, PAX6
positive regulation of gene expression	5	10.2×	0.003	PAX6, BMP4, EPHB2, FOXC1, RARG
embryonic camera-type eye development	2	126.7×	0.003	PITX2, RARG
positive regulation of programmed cell death	2	118.3×	0.003	BMP4, RARG
smooth muscle tissue development	2	110.9×	0.003	BMP4, PTCH1
commissural neuron axon guidance	2	104.3×	0.004	EPHB2, PTCH1
cell fate determination	2	98.5×	0.004	PAX6, PTCH1
axonal fasciculation	2	98.5×	0.004	EPHB2, ARHGAP35
negative regulation of stem cell proliferation	2	88.7×	0.004	PTCH1, RARG
dorsal/ventral neural tube patterning	2	84.5×	0.004	BMP4, PTCH1
blood vessel morphogenesis	2	84.5×	0.004	CYP1B1, COL4A1
neuron fate commitment	2	84.5×	0.004	PAX6, BMP4
regulation of cell size	2	80.6×	0.005	ARHGAP35, RARG
astrocyte differentiation	2	80.6×	0.005	PAX6, DAB1
negative regulation of chondrocyte differentiation	2	71.0×	0.006	BMP4, RARG

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 16

Druggability breadth: 9 of 21 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CYP1B1	PAZOPANIB
EPHB2	PONATINIB
RARG	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPHB2	30	4
CYP1B1	22	4
RARG	17	4
PRPF8	1	2
PITRM1	1	3
FOXE3	0	0
PAX6	0	0
PITX2	0	0
FOXC1	0	0
BMP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CYP1B1
INDACATEROL	4	CYP1B1
ESTRADIOL	4	CYP1B1
CANNABIDIOL	4	CYP1B1
BERBERINE	4	CYP1B1
MELATONIN	4	CYP1B1
ERYTHROMYCIN	4	CYP1B1
CARVEDILOL	4	CYP1B1
PONATINIB	4	EPHB2
FEDRATINIB	4	EPHB2
TIVOZANIB	4	EPHB2
SORAFENIB	4	EPHB2
DASATINIB ANHYDROUS	4	EPHB2
VANDETANIB	4	EPHB2
NILOTINIB	4	EPHB2
BOSUTINIB	4	EPHB2
DASATINIB	4	EPHB2
BEXAROTENE	4	RARG
AMOXICILLIN	4	RARG
ACETAMINOPHEN	4	RARG
ADAPALENE	4	RARG
TAZAROTENE	4	RARG
REGORAFENIB	4	RARG
RACECADOTRIL	4	RARG
TAMIBAROTENE	4	RARG
TRIFAROTENE	4	RARG
TRETINOIN	4	RARG
TROGLITAZONE	4	RARG
ALPROSTADIL	4	RARG
ALITRETINOIN	4	RARG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CYP1B1	408	ADMET:281, Binding:127
EPHB2	312	Binding:311, Functional:1
RARG	255	Binding:182, Functional:72, ADMET:1
PITRM1	15	Binding:15
PRPF8	8	Binding:8
PTCH1	4	Binding:4
BMP4	2	Binding:2
ARHGAP35	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PITRM1	3.4.24.56	insulysin
EPHB2	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CYP1B1	408
EPHB2	312
RARG	255

Pharmacogenomics

Cohort genes with a PharmGKB record: 19; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
PAZOPANIB	4	CYP1B1
INDACATEROL	4	CYP1B1
ESTRADIOL	4	CYP1B1
CANNABIDIOL	4	CYP1B1
BERBERINE	4	CYP1B1
MELATONIN	4	CYP1B1
ERYTHROMYCIN	4	CYP1B1
CARVEDILOL	4	CYP1B1
PONATINIB	4	EPHB2
FEDRATINIB	4	EPHB2
TIVOZANIB	4	EPHB2
SORAFENIB	4	EPHB2
DASATINIB ANHYDROUS	4	EPHB2
VANDETANIB	4	EPHB2
NILOTINIB	4	EPHB2
BOSUTINIB	4	EPHB2
DASATINIB	4	EPHB2
BEXAROTENE	4	RARG
AMOXICILLIN	4	RARG
ACETAMINOPHEN	4	RARG
ADAPALENE	4	RARG
TAZAROTENE	4	RARG
REGORAFENIB	4	RARG
RACECADOTRIL	4	RARG
TAMIBAROTENE	4	RARG
TRIFAROTENE	4	RARG
TRETINOIN	4	RARG
TROGLITAZONE	4	RARG
ALPROSTADIL	4	RARG
ALITRETINOIN	4	RARG

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CYP1B1, EPHB2, RARG
B	Phased (≥1) drug, not yet approved	2	PRPF8, PITRM1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	16	FOXE3, PAX6, PITX2, FOXC1, BMP4, ELP4, COL4A1, FAT4, FREM1, DAB1 (+6 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PITX2	0	CYP1B1
FOXC1	0	CYP1B1
FOXE3	0	—
PAX6	0	—
BMP4	2	—
ELP4	0	—
COL4A1	0	—
FAT4	0	—
FREM1	0	—
DAB1	0	—
DNAJC24	0	—
FAT1	0	—
PITRM1-AS1	0	—
ARHGAP35	1	—
ELP4-AS1	0	—
PTCH1	4	—

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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford