Isolated anophthalmia-microphthalmia syndrome

Summary

Isolated anophthalmia-microphthalmia syndrome (MONDO:0016764) is a disease (an umbrella term covering 9 Mondo subtypes) caused by ALDH1A3 (GenCC Definitive), with 14 cohort genes. The dominant Reactome pathway is Formation of the anterior neural plate (3 cohort genes).

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: ALDH1A3 (GenCC Definitive)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 14
• ClinVar variants: 10

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000		Europe	Validated
Prevalence at birth	1-9 / 100 000	2.18	France	Validated
Prevalence at birth	1-9 / 100 000	3.33	Sweden	Validated
Prevalence at birth	1-9 / 100 000	3.7	United States	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated anophthalmia-microphthalmia syndrome
Mondo ID	MONDO:0016764
Orphanet	2542
UMLS	C5679828
MedGen	1826144
GARD	0012085
Is cancer (heuristic)	no

Also known as: clinical anophthalmia · isolated anophthalmia - microphthalmia · isolated pure microphthalmia · MAC spectrum · microphthalmia-anophthalmia-coloboma spectrum · nonsyndromic anophthalmia-microphthalmia syndrome · primitive anophthalmia

Data availability: 10 ClinVar variants · 8 GenCC gene-disease records.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › isolated anophthalmia-microphthalmia syndrome

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Subtypes (9): microphthalmia, isolated, with coloboma, nanophthalmia, microphthalmia, isolated, with cataract 1, isolated microphthalmia 2, isolated microphthalmia 3, isolated microphthalmia 4, isolated microphthalmia 6, isolated microphthalmia 7, isolated microphthalmia 8

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:

5 pathogenic, 3 likely pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
978214	NM_000693.4(ALDH1A3):c.287G>A (p.Arg96His)	ALDH1A3	Pathogenic	criteria provided, single submitter
978215	NM_000693.4(ALDH1A3):c.709G>A (p.Gly237Arg)	ALDH1A3	Pathogenic	criteria provided, single submitter
4074798	NM_001123385.2(BCOR):c.4759del (p.Gln1587fs)	BCOR	Pathogenic	criteria provided, single submitter
3601838	NM_017780.4(CHD7):c.4186-2A>G	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
430969	NM_001368894.2(PAX6):c.-128-2del	PAX6	Pathogenic	criteria provided, multiple submitters, no conflicts
585293	NM_000693.4(ALDH1A3):c.1436G>A (p.Gly479Asp)	ALDH1A3	Likely pathogenic	criteria provided, single submitter
1809806	NM_024782.3(NHEJ1):c.588+18131A>G	NHEJ1	Likely pathogenic	criteria provided, single submitter
4759264	NM_033334.4(NR6A1):c.844_851dup (p.Phe284fs)	NR6A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4796492	NM_003106.4(SOX2):c.115G>T (p.Asp39Tyr)	LOC108281177	Uncertain significance	criteria provided, single submitter
2628060	NM_012431.3(SEMA3E):c.1444C>A (p.Leu482Ile)	SEMA3E	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 64 · Orphanet: 44 · 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
ALDH1A3	Definitive	Autosomal recessive	isolated anophthalmia-microphthalmia syndrome	4
OTX2	Definitive	Autosomal dominant	syndromic microphthalmia type 5	11
PRKRA	Definitive	Autosomal recessive	isolated microphthalmia 3	10
RAX	Definitive	Autosomal recessive	isolated microphthalmia 3	5
SOX2	Definitive	Autosomal dominant	anophthalmia/microphthalmia-esophageal atresia syndrome	8
VSX2	Definitive	Autosomal recessive	microphthalmia, isolated, with coloboma 3	8
RBP4	Strong	Autosomal dominant	microphthalmia, isolated, with coloboma 10	11
GDF3	Supportive	Autosomal dominant	isolated Klippel-Feil syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH1A3	Orphanet:35612	Nanophthalmos
ALDH1A3	Orphanet:98938	Colobomatous microphthalmia
SOX2	Orphanet:3157	Septo-optic dysplasia spectrum
SOX2	Orphanet:35612	Nanophthalmos
SOX2	Orphanet:77298	Anophthalmia/microphthalmia-esophageal atresia syndrome
SOX2	Orphanet:98938	Colobomatous microphthalmia
RAX	Orphanet:35612	Nanophthalmos
RAX	Orphanet:98938	Colobomatous microphthalmia
VSX2	Orphanet:98938	Colobomatous microphthalmia
GDF3	Orphanet:2345	Isolated Klippel-Feil syndrome
GDF3	Orphanet:98938	Colobomatous microphthalmia
OTX2	Orphanet:178364	Syndromic microphthalmia type 5
OTX2	Orphanet:3157	Septo-optic dysplasia spectrum
OTX2	Orphanet:35612	Nanophthalmos
OTX2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
OTX2	Orphanet:98938	Colobomatous microphthalmia
OTX2	Orphanet:990	Agnathia-holoprosencephaly-situs inversus syndrome
OTX2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PRKRA	Orphanet:210571	Dystonia 16
RBP4	Orphanet:352718	Progressive retinal dystrophy due to retinol transport defect
RBP4	Orphanet:98938	Colobomatous microphthalmia
SEMA3E	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
BCOR	Orphanet:2712	Oculofaciocardiodental syndrome
BCOR	Orphanet:457246	Clear cell sarcoma of kidney
BCOR	Orphanet:520	Acute promyelocytic leukemia
BCOR	Orphanet:568	Microphthalmia, Lenz type
NHEJ1	Orphanet:169079	Cernunnos-XLF deficiency
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

Cohort genes → proteins

14 cohort genes, 14 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	14

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH1A3	HGNC:409	ENSG00000184254	P47895	Retinaldehyde dehydrogenase 3	gencc,clinvar
SOX2	HGNC:11195	ENSG00000181449	P48431	Transcription factor SOX-2	gencc
RAX	HGNC:18662	ENSG00000134438	Q9Y2V3	Retinal homeobox protein Rx	gencc
VSX2	HGNC:1975	ENSG00000119614	P58304	Visual system homeobox 2	gencc
GDF3	HGNC:4218	ENSG00000184344	Q9NR23	Growth/differentiation factor 3	gencc
OTX2	HGNC:8522	ENSG00000165588	P32243	Homeobox protein OTX2	gencc
PRKRA	HGNC:9438	ENSG00000180228	O75569	Interferon-inducible double-stranded RNA-dependent protein kinase activator A	gencc
RBP4	HGNC:9922	ENSG00000138207	P02753	Retinol-binding protein 4	gencc
SEMA3E	HGNC:10727	ENSG00000170381	O15041	Semaphorin-3E	clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
BCOR	HGNC:20893	ENSG00000183337	Q6W2J9	BCL-6 corepressor	clinvar
NHEJ1	HGNC:25737	ENSG00000187736	Q9H9Q4	Non-homologous end-joining factor 1	clinvar
NR6A1	HGNC:7985	ENSG00000148200	Q15406	Nuclear receptor subfamily 6 group A member 1	clinvar
PAX6	HGNC:8620	ENSG00000007372	P26367	Paired box protein Pax-6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH1A3	Retinaldehyde dehydrogenase 3	Catalyzes the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively.
SOX2	Transcription factor SOX-2	Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206.
RAX	Retinal homeobox protein Rx	Plays a critical role in eye formation by regulating the initial specification of retinal cells and/or their subsequent proliferation.
VSX2	Visual system homeobox 2	Acts as a transcriptional regulator through binding to DNA at the consensus sequence 5’-[TC]TAATT[AG][AG]-3’ upstream of gene promoters.
GDF3	Growth/differentiation factor 3	Growth factor involved in early embryonic development and adipose-tissue homeostasis.
OTX2	Homeobox protein OTX2	Transcription factor probably involved in the development of the brain and the sense organs.
PRKRA	Interferon-inducible double-stranded RNA-dependent protein kinase activator A	Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis.
RBP4	Retinol-binding protein 4	Retinol-binding protein that mediates retinol transport in blood plasma.
SEMA3E	Semaphorin-3E	Plays an important role in signaling via the cell surface receptor PLXND1.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
BCOR	BCL-6 corepressor	Transcriptional corepressor.
NHEJ1	Non-homologous end-joining factor 1	DNA repair protein involved in DNA non-homologous end joining (NHEJ); it is required for double-strand break (DSB) repair and V(D)J recombination and is also involved in telomere maintenance.
NR6A1	Nuclear receptor subfamily 6 group A member 1	Orphan nuclear receptor that binds to a response element containing the sequence 5’-TCAAGGTCA-3'.
PAX6	Paired box protein Pax-6	Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas.

Protein-family classification

Druggable: 3 · Difficult: 6 · Unknown: 5 · Druggable fraction: 0.21

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	27.6×	0.107
Transcription factor	5	3.0×	0.107
Antibody/Immunoglobulin	1	2.1×	0.773
Scaffold/PPI	1	1.2×	0.846
Enzyme (other)	1	0.9×	0.846
Other/Unknown	5	0.6×	0.963

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH1A3	Enzyme (other)	yes	1.2.1.5	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH
SOX2	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_dom_sf
RAX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
VSX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
GDF3	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_CS
OTX2	Transcription factor	no		HD, Otx2_TF, Otx_TF
PRKRA	Other/Unknown	no		dsRBD_dom, PRKRA_DSRM_1, PRKRA_DSRM_2
RBP4	Other/Unknown	no		Lipocln_cytosolic_FA-bd_dom, Retinol-bd/Purpurin, Calycin
SEMA3E	Antibody/Immunoglobulin	yes		Semap_dom, Ig-like_dom, Immunoglobulin_dom
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
BCOR	Scaffold/PPI	no		Ankyrin_rpt, BCOR, PUFD
NHEJ1	Other/Unknown	no		XLF-like_N, XRCC4-like_N_sf, NHEJ_factor
NR6A1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PAX6	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

14 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)	1
broad (>20)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	4
cortical plate	3
male germ line stem cell (sensu Vertebrata) in testis	3
type B pancreatic cell	3
palpebral conjunctiva	2
pigmented layer of retina	2
ganglionic eminence	2
ventricular zone	2
biceps brachii	2
oocyte	2
secondary oocyte	2
parietal pleura	1
bronchial epithelial cell	1
nasal cavity epithelium	1
parotid gland	1
skeletal muscle tissue of biceps brachii	1
sperm	1
liver	1
right lobe of liver	1
blood vessel layer	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH1A3	244	ubiquitous	marker	palpebral conjunctiva, pigmented layer of retina, parietal pleura
SOX2	203	broad	marker	ventricular zone, bronchial epithelial cell, ganglionic eminence
RAX	29	tissue_specific	marker	parotid gland, nasal cavity epithelium, biceps brachii
VSX2	11	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, cortical plate
GDF3	82	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, type B pancreatic cell
OTX2	62	broad	marker	secondary oocyte, oocyte, pigmented layer of retina
PRKRA	294	ubiquitous	marker	sperm, skeletal muscle tissue of biceps brachii, biceps brachii
RBP4	244	broad	marker	right lobe of liver, liver, type B pancreatic cell
SEMA3E	197	broad	marker	cortical plate, calcaneal tendon, blood vessel layer
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
BCOR	265	ubiquitous	marker	buccal mucosa cell, ganglionic eminence, cortical plate
NHEJ1	189	ubiquitous	marker	rectum, primordial germ cell in gonad, mucosa of transverse colon
NR6A1	181	broad	marker	primordial germ cell in gonad, oocyte, male germ line stem cell (sensu Vertebrata) in testis
PAX6	201	broad	marker	palpebral conjunctiva, type B pancreatic cell, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX2	9,645
PAX6	4,971
CHD7	4,819
ALDH1A3	4,146
PRKRA	2,410
OTX2	2,368
BCOR	2,188
VSX2	1,484
NHEJ1	1,312
RBP4	1,143

Intra-cohort edges

A	B	Sources
CHD7	SEMA3E	string_interaction
CHD7	SOX2	intact
GDF3	SOX2	string_interaction
GDF3	VSX2	string_interaction
OTX2	RAX	string_interaction
OTX2	SOX2	string_interaction
PAX6	SOX2	biogrid_interaction, string_interaction
RAX	SOX2	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NHEJ1	Q9H9Q4	26
RBP4	P02753	23
SOX2	P48431	13
ALDH1A3	P47895	10
BCOR	Q6W2J9	5
CHD7	Q9P2D1	3
PRKRA	O75569	2
PAX6	P26367	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEMA3E	O15041	84.62
GDF3	Q9NR23	82.72
NR6A1	Q15406	78.02
RAX	Q9Y2V3	65.10
VSX2	P58304	61.65
OTX2	P32243	60.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. Enrichment computed across 14 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the anterior neural plate	3	311.4×	4e-06	SOX2, OTX2, PAX6
Formation of the posterior neural plate	2	228.4×	8e-04	SOX2, OTX2
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	2	175.7×	9e-04	SOX2, NR6A1
Retinoid metabolism disease events	1	1142.0×	0.011	RBP4
Defective visual phototransduction due to STRA6 loss of function	1	380.7×	0.026	RBP4
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	114.2×	0.049	SOX2
Small interfering RNA (siRNA) biogenesis	1	114.2×	0.049	PRKRA
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	87.8×	0.049	PAX6
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	87.8×	0.049	SOX2
Developmental Lineage of Mammary Stem Cells	1	76.1×	0.049	ALDH1A3
Germ layer formation at gastrulation	1	67.2×	0.049	SOX2
Specification of the neural plate border	1	63.4×	0.049	SOX2
Developmental Lineage of Mammary Gland Alveolar Cells	1	63.4×	0.049	ALDH1A3
Other semaphorin interactions	1	60.1×	0.049	SEMA3E
Transcriptional regulation of pluripotent stem cells	1	54.4×	0.049	SOX2
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	54.4×	0.049	ALDH1A3
Regulation of gene expression in beta cells	1	51.9×	0.049	PAX6
The canonical retinoid cycle in rods (twilight vision)	1	51.9×	0.049	RBP4
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	51.9×	0.049	PAX6
RA biosynthesis pathway	1	47.6×	0.049	ALDH1A3
MicroRNA (miRNA) biogenesis	1	45.7×	0.049	PRKRA
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	45.7×	0.049	ALDH1A3
Signaling by Retinoic Acid	1	40.8×	0.052	ALDH1A3
Semaphorin interactions	1	39.4×	0.052	SEMA3E
Transcriptional Regulation by MECP2	1	31.7×	0.062	SOX2
Gastrulation	1	25.9×	0.073	SOX2
Retinoid metabolism and transport	1	24.8×	0.073	RBP4
Deactivation of the beta-catenin transactivating complex	1	23.3×	0.075	SOX2
Nuclear Receptor transcription pathway	1	20.0×	0.084	NR6A1
MITF-M-dependent gene expression	1	18.1×	0.088	SOX2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
eye development	4	100.3×	1e-05	SOX2, GDF3, PAX6, RBP4
forebrain development	3	75.2×	9e-04	SOX2, OTX2, PAX6
primitive streak formation	2	200.6×	0.003	GDF3, OTX2
negative regulation of neuroblast proliferation	2	172.0×	0.003	VSX2, PAX6
retinal metabolic process	2	133.8×	0.005	ALDH1A3, RBP4
face development	2	114.6×	0.005	ALDH1A3, CHD7
pituitary gland development	2	92.6×	0.006	SOX2, PAX6
central nervous system development	3	24.7×	0.006	CHD7, NHEJ1, PAX6
positive regulation of transcription by RNA polymerase II	6	6.4×	0.006	SOX2, RAX, VSX2, CHD7, OTX2, PAX6
right ventricular compact myocardium morphogenesis	1	1203.7×	0.008	CHD7
pancreatic A cell development	1	1203.7×	0.008	PAX6
nucleus accumbens development	1	1203.7×	0.008	ALDH1A3
oligodendrocyte cell fate specification	1	1203.7×	0.008	PAX6
forebrain-midbrain boundary formation	1	1203.7×	0.008	PAX6
somatic motor neuron fate commitment	1	1203.7×	0.008	PAX6
specification of axis polarity	1	1203.7×	0.008	BCOR
retinol metabolic process	2	70.8×	0.008	ALDH1A3, RBP4
limb development	2	58.7×	0.008	RAX, CHD7
T cell differentiation	2	54.7×	0.008	CHD7, NHEJ1
neuroblast proliferation	2	52.3×	0.008	VSX2, PAX6
axon guidance	3	19.4×	0.008	SEMA3E, OTX2, PAX6
visual perception	3	17.0×	0.008	RAX, VSX2, PAX6
chromatin remodeling	3	15.6×	0.008	CHD7, BCOR, PAX6
negative regulation of transcription by RNA polymerase II	5	6.3×	0.008	SOX2, VSX2, BCOR, NR6A1, PAX6
inner ear morphogenesis	2	43.0×	0.009	ALDH1A3, CHD7
negative regulation of neuron differentiation	2	38.8×	0.011	SOX2, PAX6
retina development in camera-type eye	2	36.5×	0.012	CHD7, PAX6
optic cup morphogenesis involved in camera-type eye development	1	601.9×	0.012	ALDH1A3
retinol transport	1	601.9×	0.012	RBP4
negative regulation of epidermal cell differentiation	1	601.9×	0.012	GDF3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 13

Druggability breadth: 4 of 14 evidence-associated genes (29%) 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
RBP4	RETINOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RBP4	3	4
ALDH1A3	0	0
SOX2	0	0
RAX	0	0
VSX2	0	0
GDF3	0	0
OTX2	0	0
PRKRA	0	0
SEMA3E	0	0
CHD7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RETINOL	4	RBP4
TINLAREBANT	3	RBP4
FENRETINIDE	3	RBP4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALDH1A3	55	Binding:55
RBP4	32	Binding:29, Functional:3
BCOR	2	Binding:2
NR6A1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH1A3	1.2.1.5	aldehyde dehydrogenase [NAD(P)+]

Pharmacogenomics

Cohort genes with a PharmGKB record: 14; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
RETINOL	4	RBP4
TINLAREBANT	3	RBP4
FENRETINIDE	3	RBP4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RBP4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDH1A3
D	Druggable family + AlphaFold only, no drug	2	SEMA3E, NR6A1
E	Difficult family or no structure, no drug	10	SOX2, RAX, VSX2, GDF3, OTX2, PRKRA, CHD7, BCOR, NHEJ1, PAX6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDH1A3	55	—
SOX2	0	—
RAX	0	—
VSX2	0	—
GDF3	0	—
OTX2	0	—
PRKRA	0	—
SEMA3E	0	—
CHD7	0	—
BCOR	2	—
NHEJ1	0	—
NR6A1	2	—
PAX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.