Retinopathy of prematurity

Summary

Retinopathy of prematurity (MONDO:0006952) is a disease with 1 cohort gene (10 GWAS associations across 4 studies) and 149 clinical trials. Top therapeutic interventions include propranolol, benoxinate, and ketorolac.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Cohort genes: 1
• GWAS associations: 10
• ClinVar variants: 1
• Phenotypes (HPO): 15
• Clinical trials: 149

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0001518	Small for gestational age	Very frequent (80-99%)
HP:0001622	Premature birth	Very frequent (80-99%)
HP:0008046	Abnormal retinal vascular morphology	Very frequent (80-99%)
HP:0500049	Retinopathy of prematurity	Very frequent (80-99%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0001103	Abnormal macular morphology	Occasional (5-29%)
HP:0001136	Retinal arteriolar tortuosity	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0007902	Vitreous hemorrhage	Occasional (5-29%)
HP:0007917	Tractional retinal detachment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	retinopathy of prematurity
Mondo ID	MONDO:0006952
EFO	EFO:1001158
MeSH	D012178
Orphanet	90050
DOID	DOID:13025
ICD-10-CM	H35.1, H35.17
ICD-11	947283385
NCIT	C34982
SNOMED CT	415297005
UMLS	C0035344
MedGen	48438
GARD	0005695
MedDRA	10038933
NORD	1663
Is cancer (heuristic)	no

Also known as: retrolental fibroplasia · ROP · Terry syndrome

Data availability: 1 ClinVar variant · 10 GWAS associations (4 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal vascular disorder › exudative vitreoretinopathy › FZD4-related exudative vitreoretinopathy › retinopathy of prematurity

Related subtypes (1): exudative vitreoretinopathy 1

Genetics & variants

GWAS landscape

10 GWAS associations across 4 studies. Top hits map to 12 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs9978278	4e-09	LNCTSI, CLDN14	T	1.71
rs74048122	3e-08	HNRNPUP1 - KRT8P2	G	1.53
rs2058019	5e-08	GLI3	T	1.27
rs11563856	6e-08	PTTG1IP2, CLDN12, CDK14	G	1.16
rs1004464	2e-07	DNM1	G	1.29
rs72870405	1e-06	DPP4-DT - EIF3EP2	A	1.14
rs9644892	1e-06	PTPRD	G	1.1
rs62052253	1e-06	AFG3L1P, AFG3L1P	T	1.13
rs61948265	8e-06	DCLK1	A	1.14
rs78971944	9e-06	ARHGEF7	G	1.17

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90487892	Li X	2024	282	0	Genome-wide association identifies novel ROP risk loci in a multiethnic cohort.
GCST90487891	Li X	2024	197	0	Genome-wide association identifies novel ROP risk loci in a multiethnic cohort.
GCST90487893	Li X	2024	197	0	Genome-wide association identifies novel ROP risk loci in a multiethnic cohort.
GCST90487894	Li X	2024	51	0	Genome-wide association identifies novel ROP risk loci in a multiethnic cohort.

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	10

MAF distribution

Bucket	Variants
common (>=0.05)	10
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	9
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs9978278	21	36522423	C>T	0.05	intron_variant	LNCTSI, CLDN14	4e-09	Tier 4: intronic/intergenic
rs74048122	14	43420342	A>G	0.05	intron_variant	HNRNPUP1 - KRT8P2	3e-08	Tier 4: intronic/intergenic
rs2058019	7	42187113	A>G,T	0.06	intron_variant	GLI3	5e-08	Tier 4: intronic/intergenic
rs11563856	7	90512541	T>A,G	0.17	intron_variant	PTTG1IP2, CLDN12, CDK14	6e-08	Tier 4: intronic/intergenic
rs1004464	9	128241398	A>C,G	0.05	intron_variant	DNM1	2e-07	Tier 4: intronic/intergenic
rs72870405	2	162080573	T>A,C,G	0.13	intergenic_variant	DPP4-DT - EIF3EP2	1e-06	Tier 4: intronic/intergenic
rs9644892	9	8800078	A>G	0.37	intron_variant	PTPRD	1e-06	Tier 4: intronic/intergenic
rs62052253	16	89982481	C>T	0.22	intron_variant	AFG3L1P, AFG3L1P	1e-06	Tier 4: intronic/intergenic
rs61948265	13	35984893	G>A,T	0.14	intron_variant	DCLK1	8e-06	Tier 4: intronic/intergenic
rs78971944	13	111159626	A>G	0.09	intron_variant	ARHGEF7	9e-06	Tier 4: intronic/intergenic

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
5489	NM_012193.4(FZD4):c.766A>G (p.Ile256Val)	FZD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FZD4	Orphanet:891	Familial exudative vitreoretinopathy
FZD4	Orphanet:90050	Retinopathy of prematurity
FZD4	Orphanet:91495	Persistent hyperplastic primary vitreous

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
FZD4	HGNC:4042	ENSG00000174804	Q9ULV1	Frizzled-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FZD4	Frizzled-4	Receptor for Wnt proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FZD4	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM

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
adipose tissue	1
right lung	1
subcutaneous adipose tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FZD4	243	ubiquitous	marker	adipose tissue, subcutaneous adipose tissue, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FZD4	1,869

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FZD4	Q9ULV1	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Signaling by RNF43 mutants	1	1268.9×	0.005	FZD4
WNT5A-dependent internalization of FZD4	1	761.3×	0.005	FZD4
Regulation of FZD by ubiquitination	1	519.1×	0.005	FZD4
Asymmetric localization of PCP proteins	1	203.9×	0.007	FZD4
Class B/2 (Secretin family receptors)	1	190.3×	0.007	FZD4
Ca2+ pathway	1	178.4×	0.007	FZD4
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.011	FZD4
Clathrin-mediated endocytosis	1	85.2×	0.012	FZD4

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
cerebellum vasculature morphogenesis	1	16852.0×	0.001	FZD4
progesterone secretion	1	8426.0×	0.001	FZD4
Wnt signaling pathway, calcium modulating pathway	1	4213.0×	0.001	FZD4
extracellular matrix-cell signaling	1	3370.4×	0.001	FZD4
retina vasculature morphogenesis in camera-type eye	1	3370.4×	0.001	FZD4
Norrin signaling pathway	1	3370.4×	0.001	FZD4
regulation of vascular endothelial growth factor receptor signaling pathway	1	2808.7×	0.001	FZD4
locomotion involved in locomotory behavior	1	2407.4×	0.001	FZD4
retinal blood vessel morphogenesis	1	2407.4×	0.001	FZD4
positive regulation of neuron projection arborization	1	2106.5×	0.001	FZD4
establishment of blood-brain barrier	1	1404.3×	0.002	FZD4
endothelial cell differentiation	1	1123.5×	0.002	FZD4
negative regulation of cell-substrate adhesion	1	1053.2×	0.002	FZD4
positive regulation of dendrite morphogenesis	1	887.0×	0.002	FZD4
non-canonical Wnt signaling pathway	1	581.1×	0.003	FZD4
substrate adhesion-dependent cell spreading	1	343.9×	0.005	FZD4
vasculogenesis	1	255.3×	0.007	FZD4
cellular response to retinoic acid	1	234.1×	0.007	FZD4
cellular response to leukemia inhibitory factor	1	159.0×	0.009	FZD4
canonical Wnt signaling pathway	1	153.2×	0.009	FZD4
cell population proliferation	1	102.8×	0.012	FZD4
sensory perception of sound	1	100.9×	0.012	FZD4
neuron differentiation	1	100.3×	0.012	FZD4
Wnt signaling pathway	1	99.7×	0.012	FZD4
response to hypoxia	1	95.8×	0.012	FZD4
angiogenesis	1	62.4×	0.017	FZD4
positive regulation of cell migration	1	61.7×	0.017	FZD4
positive regulation of DNA-templated transcription	1	27.9×	0.037	FZD4
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	FZD4

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

15 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Aflibercept	Phase 3
Bevacizumab	Phase 3
Dexmedetomidine	Phase 3
Inositol	Phase 3
Oxygen	Phase 3
Ranibizumab	Phase 3
Sodium Chloride	Phase 3
Doconexent	Phase 2
Fasudil	Phase 2
Fish Oil Triglycerides	Phase 2
Ibuprofen	Phase 2
Ketorolac	Phase 2
Mecasermin	Phase 2
Mecasermin Rinfabate	Phase 2
Propranolol	Phase 2

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FZD4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FZD4	7	Functional:6, Binding:1

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	1	FZD4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FZD4	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 149.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	92
PHASE2	16
PHASE3	15
PHASE4	10
PHASE2/PHASE3	6
PHASE1	5
PHASE1/PHASE2	4
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00417404	PHASE4	COMPLETED	Vitamin A and Very Low Birthweight Babies (VitAL)
NCT00500396	PHASE4	TERMINATED	Vascular Endothelial Growth Factor in Stage V ROP
NCT00563121	PHASE4	WITHDRAWN	VEGF Levels in Aqueous, Vitreous and Subretinal Fluid in ROP Stage IV and V
NCT00634972	PHASE4	TERMINATED	Efficient Study of ACULAR in Inhibiting Proliferative Retinopathy in Prematurity
NCT00921544	PHASE4	COMPLETED	Sucrose Analgesia for the Reduction of Pain During Retinopathy of Prematurity Screening
NCT04050488	PHASE4	UNKNOWN	Zinc Supplementation on Very Low Birth Weight Infant
NCT04623684	PHASE4	COMPLETED	Efficacy and Safety of Mydriatic Microdrops Compared With Standard Drops for Retinopathy of Prematurity (ROP) Screening: a Pilot Randomized Clinical Trial
NCT04838665	PHASE4	COMPLETED	Changes in Vital Signs and Pupil Diameter Related to Pharmacologic Mydriasis in Premature Infants: A Randomized Double Blind Clinical Study
NCT04902859	PHASE4	UNKNOWN	Clonidine as Pain Relief During ROP Eye Examinations
NCT05043077	PHASE4	COMPLETED	Efficacy and Safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening
NCT00346814	PHASE2/PHASE3	RECRUITING	Antiangiogenic Therapy With Bevacizumab in Retinopathy of Prematurity. Structural Outcome
NCT06067958	PHASE3	RECRUITING	Intranasal Dexmedetomidine for Pain Management During Screening for Retinopathy of Prematurity
NCT00000156	PHASE3	COMPLETED	The Effects of Light Reduction on Retinopathy of Prematurity (Light-ROP)
NCT00027222	PHASE2/PHASE3	UNKNOWN	The Early Treatment for Retinopathy of Prematurity Study (ETROP)
NCT00233324	PHASE3	COMPLETED	Surfactant Positive Airway Pressure and Pulse Oximetry Trial
NCT00254176	PHASE2/PHASE3	UNKNOWN	Cysteine Supplementation in Critically Ill Neonates
NCT00623220	PHASE3	COMPLETED	Inhaled Nitrous Oxide for Pain Relief During Eye Exam in the Pre-term Infant
NCT01079715	PHASE2/PHASE3	COMPLETED	Safety and Efficacy of Propranolol in Newborns With Retinopathy of Prematurity
NCT01203436	PHASE2/PHASE3	COMPLETED	Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity
NCT01954082	PHASE3	TERMINATED	Inositol to Reduce Retinopathy of Prematurity
NCT02375971	PHASE3	COMPLETED	RAINBOW Study: RAnibizumab Compared With Laser Therapy for the Treatment of INfants BOrn Prematurely With Retinopathy of Prematurity
NCT02640664	PHASE3	COMPLETED	Rainbow Extension Study
NCT02760472	PHASE3	COMPLETED	A Fatty Acids Study in Preventing Retinopathy of Prematurity
NCT04004208	PHASE3	COMPLETED	Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy
NCT04015180	PHASE3	COMPLETED	Extension Study to Evaluate the Long-term Outcomes of Subjects in Study 20090
NCT04101721	PHASE3	COMPLETED	Study to Assess the Efficacy, Safety, and Tolerability of Intravitreal Aflibercept Compared to Laser Photocoagulation in Patients With Retinopathy of Prematurity
NCT04191954	PHASE2/PHASE3	UNKNOWN	Fasudil Eye Drop in Retinopathy Of Prematurity(ROP)
NCT04634604	PHASE3	TERMINATED	A Randomized Trial of Low-Dose Bevacizumab vs Laser for Type 1 ROP
NCT05701124	PHASE3	COMPLETED	Intravitreal Ranibizumab Injection for Aggressive Versus Type 1 Prethreshold Retinopathy of Prematurity
NCT05712642	PHASE3	COMPLETED	A Dosing Study of Intravitreal Bevacizumab for Retinopathy of Prematurity
NCT06461975	PHASE3	COMPLETED	Effect of Benoxinate Hydrochloride Eye Drops on The Premature Infant Pain Profile Score During Retinopathy of Prematurity Screening
NCT03083431	PHASE2	RECRUITING	Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity
NCT03253263	PHASE2	RECRUITING	A Clinical Efficacy and Safety Study of OHB-607 in Preventing Bronchopulmonary Dysplasia in Extremely Premature Infants
NCT04634578	PHASE2	ACTIVE_NOT_RECRUITING	Bevacizumab Treatment For Type 1 ROP
NCT07112430	PHASE1/PHASE2	NOT_YET_RECRUITING	Fentanyl Intranasal for Retinopathy of Prematurity Screening in Preterm Infants
NCT00349726	PHASE2	COMPLETED	Single-Dose Intravenous Inositol Pharmacokinetics in Preterm Infants
NCT00622726	PHASE2	UNKNOWN	Bevacizumab Eliminates the Angiogenic Threat for Retinopathy of Prematurity
NCT00910234	PHASE1/PHASE2	UNKNOWN	Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants
NCT01030575	PHASE2	COMPLETED	Multi-dose Pharmacokinetics and Dose Ranging of Inositol in Premature Infants (INS-2)
NCT01096784	PHASE2	COMPLETED	IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PROPRANOLOL	4	3
BENOXINATE	4	2
KETOROLAC	4	2
TROPICAMIDE	4	2
WATER	4	2
CAFFEINE CITRATE	4	1
FISH OIL TRIGLYCERIDES	4	1
MECASERMIN RINFABATE	4	1
OXYGEN	4	1
PROPARACAINE	4	1
RETINOL	4	1
VITAMIN A PALMITATE	4	1
ZINC SULFATE	4	1
CONBERCEPT	3	1
DOCONEXENT	3	1
INOSITOL	3	1
DEXPROPRANOLOL	2	1
RINFABATE	2	1
CHEMBL1457550	0	2
CHEMBL1950780	0	1
CHEMBL4439413	0	1