Disorder of visual system

Summary

Disorder of visual system (MONDO:0024458) is a disease (an umbrella term covering 30 Mondo subtypes) caused by variants in PITX2 and PITX3, with 3 cohort genes (1 GWAS associations across 8 studies).

At a glance

• Causal genes: PITX2 (GenCC Strong), PITX3 (GenCC Strong)
• Umbrella term: 30 Mondo subtypes
• Cohort genes: 3
• GWAS associations: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	disorder of visual system
Mondo ID	MONDO:0024458
SNOMED CT	128127008
Anatomy (UBERON)	UBERON:0002104
Is cancer (heuristic)	no

Also known as: disease of visual system · disease or disorder of visual system · disorder of visual system · visual system disease · visual system disease or disorder · visual system disorder

Data availability: 1 GWAS association (8 studies) · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 30 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of visual system

Related subtypes (18): disorder of orbital region, integumentary system disorder, musculoskeletal system disorder, urinary system disorder, syndromic disease, auditory system disorder, breast disorder, connective tissue disorder, digestive system disorder, cardiovascular disorder, reproductive system disorder, immune system disorder, nervous system disorder, respiratory system disorder, endocrine system disorder, hematologic disorder, mouth disorder, otorhinolaryngologic disease

Subtypes (30): oculomotor nerve paralysis, optic nerve disorder, myopathy of extraocular muscle, eye disorder, Stern-Lubinsky-Durrie syndrome, jaw-winking syndrome, aniridia-renal agenesis-psychomotor retardation syndrome, colobomatous optic disc-macular atrophy-chorioretinopathy syndrome, cortical blindness-intellectual disability-polydactyly syndrome, Joubert syndrome with oculorenal defect, Mietens syndrome, EEC syndrome, spastic ataxia-corneal dystrophy syndrome, oculogastrointestinal muscular dystrophy, CHIME syndrome, Kearns-Sayre syndrome, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, RHYNS syndrome, colobomatous macrophthalmia-microcornea syndrome, microtia-eye coloboma-imperforation of the nasolacrimal duct syndrome, intellectual disability-strabismus syndrome, familial progressive retinal dystrophy-iris coloboma-congenital cataract syndrome, ankyloblepharon filiforme-imperforate anus syndrome, cataract-glaucoma syndrome, Joubert syndrome with ocular defect, microcephaly-microcornea syndrome, Seemanova type, osteochondrodysplatic nanism-deafness-retinitis pigmentosa syndrome, ocular albinism, maternally-inherited progressive external ophthalmoplegia, vision disorder

Genetics & variants

GWAS landscape

1 GWAS associations across 8 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs146487080	9e-08	RPS27P18 - TEX36-AS1	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477696	Verma A	2024	50,666	345,098	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477695	Verma A	2024	14,464	91,031	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481109	Verma A	2024	14,464	91,031	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477693	Verma A	2024	6,526	46,093	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435994	Zhou W	2018	3,307	405,654	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90473443	UK Biobank Whole-Genome Sequencing Consortium	2025	2,109	456,331	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90651824	Liu TY	2025	1,346	213,222	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90477694	Verma A	2024	704	5,369	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs146487080	10	125509904	C>A,T	0.05	intergenic_variant	RPS27P18 - TEX36-AS1	9e-08	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 11 · 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	Strong	Autosomal dominant	disorder of visual system	15
PITX3	Strong	Autosomal dominant	disorder of visual system	7
OPN1MW	Moderate	X-linked	disorder of visual system	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OPN1MW	Orphanet:16	Blue cone monochromatism
OPN1MW	Orphanet:1872	Cone rod dystrophy
OPN1MW	Orphanet:90001	X-linked cone dysfunction syndrome with myopia
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
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
OPN1MW	HGNC:4206	ENSG00000268221	P04001	Medium-wave-sensitive opsin 1	gencc
PITX2	HGNC:9005	ENSG00000164093	Q99697	Pituitary homeobox 2	gencc
PITX3	HGNC:9006	ENSG00000107859	O75364	Pituitary homeobox 3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OPN1MW	Medium-wave-sensitive opsin 1	Visual pigments are the light-absorbing molecules that mediate vision.
PITX2	Pituitary homeobox 2	May play a role in myoblast differentiation.
PITX3	Pituitary homeobox 3	Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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
GPCR	1	8.0×	0.120

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OPN1MW	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin
PITX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
PITX3	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)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1
biceps brachii	1
gingiva	1
gingival epithelium	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OPN1MW	16		yes	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, sural nerve
PITX2	166	broad	marker	gingiva, biceps brachii, gingival epithelium
PITX3	64	tissue_specific	yes	hindlimb stylopod muscle, triceps brachii, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PITX2	2,389
PITX3	1,186
OPN1MW	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OPN1MW	P04001	3
PITX2	Q99697	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PITX3	O75364	63.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 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
Defective visual phototransduction due to OPN1MW loss of function	1	5710.0×	9e-04	OPN1MW
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	1427.5×	0.002	PITX2
The retinoid cycle in cones (daylight vision)	1	815.7×	0.002	OPN1MW
Opsins	1	634.4×	0.002	OPN1MW
G alpha (i) signalling events	1	19.5×	0.051	OPN1MW

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
subthalamic nucleus development	1	5617.3×	0.002	PITX2
superior vena cava morphogenesis	1	5617.3×	0.002	PITX2
negative regulation of gliogenesis	1	2808.7×	0.002	PITX3
hypothalamus cell migration	1	2808.7×	0.002	PITX2
prolactin secreting cell differentiation	1	2808.7×	0.002	PITX2
left lung morphogenesis	1	2808.7×	0.002	PITX2
pulmonary vein morphogenesis	1	2808.7×	0.002	PITX2
cell proliferation involved in outflow tract morphogenesis	1	2808.7×	0.002	PITX2
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
anatomical structure morphogenesis	2	92.8×	0.002	PITX2, PITX3
pulmonary myocardium development	1	1872.4×	0.002	PITX2
vascular associated smooth muscle cell differentiation	1	1872.4×	0.002	PITX2
deltoid tuberosity development	1	1872.4×	0.002	PITX2
endodermal digestive tract morphogenesis	1	1872.4×	0.002	PITX2
atrioventricular valve development	1	1404.3×	0.003	PITX2
somatotropin secreting cell differentiation	1	1404.3×	0.003	PITX2
extraocular skeletal muscle development	1	936.2×	0.003	PITX2
absorption of visible light	1	936.2×	0.003	OPN1MW
embryonic heart tube left/right pattern formation	1	936.2×	0.003	PITX2
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	802.5×	0.003	PITX2
atrial cardiac muscle tissue morphogenesis	1	802.5×	0.003	PITX2
hair cell differentiation	1	702.2×	0.004	PITX2
iris morphogenesis	1	624.1×	0.004	PITX2
ventricular cardiac muscle cell development	1	510.7×	0.005	PITX2
lens morphogenesis in camera-type eye	1	432.1×	0.005	PITX3
embryonic camera-type eye development	1	401.2×	0.005	PITX2
left/right axis specification	1	401.2×	0.005	PITX2
lens fiber cell differentiation	1	351.1×	0.006	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
OPN1MW	0	0
PITX2	0	0
PITX3	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	1	OPN1MW
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PITX2, PITX3

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)
OPN1MW	0	—
PITX2	0	—
PITX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.