Severe early-childhood-onset retinal dystrophy

Summary

Severe early-childhood-onset retinal dystrophy (MONDO:0009549) is a disease caused by ABCA4 (GenCC Definitive), with 14 cohort genes and 14 clinical trials. The dominant Reactome pathway is The canonical retinoid cycle in rods (twilight vision) (4 cohort genes). Top therapeutic interventions include tinlarebant and stg-001.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ABCA4 (GenCC Definitive)
• Cohort genes: 14
• ClinVar variants: 711
• Phenotypes (HPO): 33
• Clinical trials: 14

Clinical features

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000546	Retinal degeneration	Frequent (30-79%)
HP:0000662	Nyctalopia	Frequent (30-79%)
HP:0000550	Undetectable electroretinogram	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0007695	Abnormal pupillary light reflex	Frequent (30-79%)
HP:0007994	Peripheral visual field loss	Frequent (30-79%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0012426	Optic disc drusen	Frequent (30-79%)
HP:0007843	Attenuation of retinal blood vessels	Frequent (30-79%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0001103	Abnormal macular morphology	Frequent (30-79%)
HP:0007814	Retinal pigment epithelial mottling	Frequent (30-79%)
HP:0007737	Bone spicule pigmentation of the retina	Frequent (30-79%)
HP:0000551	Color vision defect	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0007722	Retinal pigment epithelial atrophy	Occasional (5-29%)
HP:0000622	Blurred vision	Occasional (5-29%)
HP:0011488	Abnormal corneal endothelium morphology	Occasional (5-29%)
HP:0011484	Posterior synechiae of the anterior chamber	Occasional (5-29%)
HP:0007787	Posterior subcapsular cataract	Occasional (5-29%)
HP:0001116	Macular coloboma	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0012434	Delayed social development	Occasional (5-29%)
HP:0002172	Postural instability	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0000577	Exotropia	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000533	Chorioretinal atrophy	Occasional (5-29%)
HP:0002317	Unsteady gait	Occasional (5-29%)
HP:0011342	Mild global developmental delay	Occasional (5-29%)
HP:0007793	Granular macular appearance	Occasional (5-29%)
HP:0012230	Rhegmatogenous retinal detachment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe early-childhood-onset retinal dystrophy
Mondo ID	MONDO:0009549
OMIM	248200
Orphanet	364055
DOID	DOID:0061241
SNOMED CT	716663009
UMLS	C1855465
MedGen	383691
GARD	0021565
Is cancer (heuristic)	no

Also known as: early-onset severe retinal dystrophy · EOSRD · SECORD · Stargardt disease 1 · Stargardt disease type 1 · STGD1

Data availability: 711 ClinVar variants · 8 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › macular degeneration › Stargardt disease › severe early-childhood-onset retinal dystrophy

Related subtypes (3): Stargardt disease 3, Stargardt disease 4, Stargardt disease 5

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:

132 pathogenic/likely pathogenic, 128 pathogenic, 110 uncertain significance, 98 conflicting classifications of pathogenicity, 88 likely pathogenic, 28 benign, 11 benign/likely benign, 4 likely benign, 1 pathogenic/likely pathogenic/established risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
3897888	NM_000350.2:c.[3149G>A];[1928T>G]		Pathogenic	criteria provided, single submitter
424760	NM_000350.2(ABCA4):c.[2588G>C];[5882G>A]		Pathogenic	criteria provided, single submitter
424771	NM_019098.4(CNGB3):c.[1193A>G];[1208G>A]		Pathogenic	criteria provided, single submitter
7901	NM_000350.2(ABCA4):c.[1622T>C;3113C>T]		Pathogenic	reviewed by expert panel
1000328	NM_000350.3(ABCA4):c.5691G>T (p.Gln1897His)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1001082	NM_000350.3(ABCA4):c.1019A>C (p.Tyr340Ser)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1024633	NM_000350.3(ABCA4):c.4217A>G (p.His1406Arg)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1040597	NM_000350.3(ABCA4):c.5324T>A (p.Ile1775Asn)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048125	NM_000350.3(ABCA4):c.4383G>C (p.Trp1461Cys)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048142	NM_000350.3(ABCA4):c.5377G>A (p.Val1793Met)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048143	NM_000350.3(ABCA4):c.3523-1G>A	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048145	NM_000350.3(ABCA4):c.6122G>A (p.Gly2041Asp)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048153	NM_000350.3(ABCA4):c.428del (p.Pro143fs)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048167	NM_000350.3(ABCA4):c.2932G>A (p.Gly978Ser)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048172	NM_000350.3(ABCA4):c.5311G>A (p.Gly1771Arg)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1062657	NM_000350.3(ABCA4):c.2294GTG[1] (p.Gly766del)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065650	NM_000350.3(ABCA4):c.5461-1G>T	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1065685	NM_000350.3(ABCA4):c.2292_2295delinsAGG (p.Cys764_Ser765delinsTer)	ABCA4	Pathogenic	criteria provided, single submitter
1065733	NM_000350.3(ABCA4):c.442+2T>A	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067357	NM_000350.3(ABCA4):c.3522+1G>A	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069499	NM_000350.3(ABCA4):c.2069del (p.Gly690fs)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1070817	NM_000350.3(ABCA4):c.1749_1750del (p.Lys583fs)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1073023	NM_000350.3(ABCA4):c.4501G>T (p.Glu1501Ter)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1073468	NM_000350.3(ABCA4):c.1761-2A>G	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073469	NM_000350.3(ABCA4):c.1561del (p.Val521fs)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076593	NM_000350.3(ABCA4):c.1391T>A (p.Leu464Ter)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1184970	NM_000350.3(ABCA4):c.3287C>T (p.Ser1096Leu)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1213957	NM_000350.3(ABCA4):c.2922_2949del (p.Ile975fs)	ABCA4	Pathogenic	criteria provided, single submitter
1213969	NM_000350.3(ABCA4):c.3296C>G (p.Ser1099Ter)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1275763	NM_000350.3(ABCA4):c.5578C>T (p.Arg1860Trp)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 50 · Orphanet: 48 · 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
ABCA4	Definitive	Autosomal recessive	severe early-childhood-onset retinal dystrophy	12
CNGB3	Supportive	Autosomal dominant	cone dystrophy	5
LCA5	Supportive	Autosomal recessive	severe early-childhood-onset retinal dystrophy	6
LRAT	Supportive	Autosomal recessive	severe early-childhood-onset retinal dystrophy	7
RPE65	Supportive	Autosomal recessive	severe early-childhood-onset retinal dystrophy	13
SPATA7	Supportive	Autosomal recessive	severe early-childhood-onset retinal dystrophy	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CNGB3	Orphanet:1871	Progressive cone dystrophy
CNGB3	Orphanet:49382	Achromatopsia
CNGB3	Orphanet:827	Stargardt disease
ABCA4	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:827	Stargardt disease
RPE65	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
RPE65	Orphanet:65	Leber congenital amaurosis
RPE65	Orphanet:791	Retinitis pigmentosa
SPATA7	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
SPATA7	Orphanet:65	Leber congenital amaurosis
SPATA7	Orphanet:791	Retinitis pigmentosa
LCA5	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
LCA5	Orphanet:65	Leber congenital amaurosis
LRAT	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
LRAT	Orphanet:65	Leber congenital amaurosis
LRAT	Orphanet:791	Retinitis pigmentosa
RHO	Orphanet:215	Congenital stationary night blindness
RHO	Orphanet:52427	Retinitis punctata albescens
RHO	Orphanet:791	Retinitis pigmentosa
BEST1	Orphanet:1243	Best vitelliform macular dystrophy
BEST1	Orphanet:139455	Autosomal recessive bestrophinopathy
BEST1	Orphanet:263347	MRCS syndrome
BEST1	Orphanet:3086	Autosomal dominant vitreoretinochoroidopathy
BEST1	Orphanet:35612	Nanophthalmos
BEST1	Orphanet:791	Retinitis pigmentosa
BEST1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
CAPN5	Orphanet:329211	Autosomal dominant neovascular inflammatory vitreoretinopathy
CRB1	Orphanet:251295	Pigmented paravenous retinochoroidal atrophy
CRB1	Orphanet:35612	Nanophthalmos
CRB1	Orphanet:65	Leber congenital amaurosis
CRB1	Orphanet:791	Retinitis pigmentosa
MFSD8	Orphanet:1872	Cone rod dystrophy
MFSD8	Orphanet:228366	CLN7 disease
ABCB4	Orphanet:69663	Low phospholipid-associated cholelithiasis
ABCB4	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB4	Orphanet:79305	Progressive familial intrahepatic cholestasis type 3
LRP5	Orphanet:178377	Osteosclerosis-developmental delay-craniosynostosis syndrome
LRP5	Orphanet:2783	Autosomal dominant osteopetrosis type 1
LRP5	Orphanet:2788	Osteoporosis-pseudoglioma syndrome
LRP5	Orphanet:2790	Endosteal hyperostosis, Worth type
LRP5	Orphanet:2924	Isolated polycystic liver disease
LRP5	Orphanet:3416	Hyperostosis corticalis generalisata
LRP5	Orphanet:498481	LRP5-related primary osteoporosis
LRP5	Orphanet:891	Familial exudative vitreoretinopathy
LRP5	Orphanet:90050	Retinopathy of prematurity
BBS1	Orphanet:110	Bardet-Biedl syndrome
BBS1	Orphanet:791	Retinitis pigmentosa

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
CNGB3	HGNC:2153	ENSG00000170289	Q9NQW8	Cyclic nucleotide-gated channel beta-3	gencc,clinvar
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	gencc,clinvar
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	gencc
SPATA7	HGNC:20423	ENSG00000042317	Q9P0W8	Spermatogenesis-associated protein 7	gencc
LCA5	HGNC:31923	ENSG00000135338	Q86VQ0	Lebercilin	gencc
LRAT	HGNC:6685	ENSG00000121207	O95237	Lecithin retinol acyltransferase	gencc
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	clinvar
CAPN5	HGNC:1482	ENSG00000149260	O15484	Calpain-5	clinvar
CRB1	HGNC:2343	ENSG00000134376	P82279	Protein crumbs homolog 1	clinvar
MFSD8	HGNC:28486	ENSG00000164073	Q8NHS3	Major facilitator superfamily domain-containing protein 8	clinvar
ABCB4	HGNC:45	ENSG00000005471	P21439	Phosphatidylcholine translocator ABCB4	clinvar
LRP5	HGNC:6697	ENSG00000162337	O75197	Low-density lipoprotein receptor-related protein 5	clinvar
BBS1	HGNC:966	ENSG00000174483	Q8NFJ9	BBSome complex member BBS1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNGB3	Cyclic nucleotide-gated channel beta-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
ABCA4	Retinal-specific phospholipid-transporting ATPase ABCA4	Flippase that catalyzes in an ATP-dependent manner the transport of retinal-phosphatidylethanolamine conjugates like 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leafl…
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
SPATA7	Spermatogenesis-associated protein 7	Involved in the maintenance of both rod and cone photoreceptor cells.
LCA5	Lebercilin	Involved in intraflagellar protein (IFT) transport in photoreceptor cilia.
LRAT	Lecithin retinol acyltransferase	Transfers the acyl group from the sn-1 position of phosphatidylcholine to all-trans retinol, producing all-trans retinyl esters.
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.
BEST1	Bestrophin-1	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).
CAPN5	Calpain-5	Calcium-regulated non-lysosomal thiol-protease.
CRB1	Protein crumbs homolog 1	Plays a role in photoreceptor morphogenesis in the retina.
MFSD8	Major facilitator superfamily domain-containing protein 8	Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function.
ABCB4	Phosphatidylcholine translocator ABCB4	Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion.
LRP5	Low-density lipoprotein receptor-related protein 5	Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins.
BBS1	BBSome complex member BBS1	The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.

Protein-family classification

Druggable: 8 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.57

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
Transporter	3	16.7×	0.004
Ion channel	1	8.0×	0.356
Protease	1	2.6×	0.492
Enzyme (other)	2	1.7×	0.492
GPCR	1	1.7×	0.540
Other/Unknown	6	0.8×	0.893

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CNGB3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase
SPATA7	Other/Unknown	no		SPATA7
LCA5	Other/Unknown	no		Lebercilin-like, Lebercilin_dom
LRAT	Enzyme (other)	yes	2.3.1.135	LRAT_dom, LRAT
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like
CAPN5	Protease	yes	3.4.22.B25	C2_dom, Pept_cys_AS, Peptidase_C2_calpain_cat
CRB1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
MFSD8	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
ABCB4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
LRP5	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt
BBS1	Other/Unknown	no		Quinoprotein_ADH-like_sf, BBS1, BBS1_N

Expression context

Cohort genes with no expression data: 0.

13 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)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	5
male germ line stem cell (sensu Vertebrata) in testis	4
diaphragm	2
primordial germ cell in gonad	2
mucosa of transverse colon	2
right lobe of liver	2
retina	1
left testis	1
right testis	1
sperm	1
bronchial epithelial cell	1
bronchus	1
mucosa of paranasal sinus	1
neuron projection bundle connecting eye with brain	1
optic choroid	1
inferior olivary complex	1
lateral globus pallidus	1
gall bladder	1
rectum	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CNGB3	161	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, diaphragm
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
RPE65	92	tissue_specific	marker	pigmented layer of retina, retina, male germ line stem cell (sensu Vertebrata) in testis
SPATA7	263	ubiquitous	marker	right testis, sperm, left testis
LCA5	214	ubiquitous	marker	mucosa of paranasal sinus, bronchial epithelial cell, bronchus
LRAT	149	broad	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
RHO	38	tissue_specific	marker	optic choroid, neuron projection bundle connecting eye with brain, diaphragm
BEST1	209	ubiquitous	marker	pigmented layer of retina, lateral globus pallidus, inferior olivary complex
CAPN5	224	ubiquitous	marker	mucosa of transverse colon, rectum, gall bladder
CRB1	163	broad	marker	ganglionic eminence, ventricular zone, endothelial cell
MFSD8	256	ubiquitous	marker	oviduct epithelium, adrenal tissue, calcaneal tendon
ABCB4	188	broad	marker	right lobe of liver, secondary oocyte, oocyte
LRP5	224	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, ascending aorta
BBS1	134	ubiquitous	yes	right uterine tube, left ovary, ovary

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RHO	3,578
LRP5	2,619
ABCB4	2,333
BBS1	2,189
ABCA4	1,532
RPE65	1,414
MFSD8	1,405
CRB1	1,075
LCA5	1,027
CAPN5	972

Intra-cohort edges

A	B	Sources
ABCA4	BEST1	string_interaction
ABCA4	CNGB3	string_interaction
ABCA4	RHO	string_interaction
ABCA4	RPE65	string_interaction
BEST1	RPE65	string_interaction
CNGB3	RPE65	string_interaction
LCA5	LRAT	string_interaction
LCA5	RPE65	string_interaction
LCA5	SPATA7	string_interaction
LRAT	RPE65	string_interaction
LRAT	SPATA7	string_interaction
RHO	RPE65	string_interaction
RPE65	SPATA7	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BEST1	O76090	19
CNGB3	Q9NQW8	9
ABCA4	P78363	8
RHO	P08100	4
ABCB4	P21439	4
CAPN5	O15484	1
CRB1	P82279	1
BBS1	Q8NFJ9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPE65	Q16518	95.34
LRAT	O95237	83.69
MFSD8	Q8NHS3	83.20
LRP5	O75197	78.65
LCA5	Q86VQ0	64.05
SPATA7	Q9P0W8	58.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 14 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The canonical retinoid cycle in rods (twilight vision)	4	230.7×	6e-08	ABCA4, RHO, RPE65, LRAT
Retinoid cycle disease events	2	634.4×	4e-05	ABCA4, LRAT
Diseases associated with visual transduction	2	634.4×	4e-05	ABCA4, LRAT
Diseases of the neuronal system	2	634.4×	4e-05	ABCA4, LRAT
Visual phototransduction	3	86.5×	4e-05	ABCA4, RPE65, LRAT
Sensory Perception	3	31.7×	7e-04	ABCA4, RPE65, LRAT
Defective ABCB4 causes PFIC3, ICP3 and GBD1	1	1268.9×	0.004	ABCB4
Defective visual phototransduction due to ABCA4 loss of function	1	1268.9×	0.004	ABCA4
Defective visual phototransduction due to LRAT loss of function	1	634.4×	0.008	LRAT
ABC-family protein mediated transport	2	27.0×	0.010	ABCA4, ABCB4
Disease	4	5.8×	0.013	ABCA4, ABCB4, LRAT, LRP5
Transport of small molecules	3	8.4×	0.016	ABCA4, BEST1, ABCB4
Signaling by LRP5 mutants	1	181.3×	0.019	LRP5
Opsins	1	141.0×	0.021	RHO
Signaling by RNF43 mutants	1	141.0×	0.021	LRP5
Activation of the phototransduction cascade	1	105.7×	0.026	RHO
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	79.3×	0.032	LRP5
Signaling by WNT in cancer	1	66.8×	0.036	LRP5
Regulation of FZD by ubiquitination	1	57.7×	0.038	LRP5
VxPx cargo-targeting to cilium	1	57.7×	0.038	RHO
BBSome-mediated cargo-targeting to cilium	1	55.2×	0.038	BBS1
ABC transporter disorders	1	48.8×	0.041	ABCB4
Metabolism of fat-soluble vitamins	1	42.3×	0.045	LRAT
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	39.6×	0.046	LRP5
Inactivation, recovery and regulation of the phototransduction cascade	1	35.2×	0.049	RHO
Cargo trafficking to the periciliary membrane	1	27.6×	0.058	BBS1
Retinoid metabolism and transport	1	27.6×	0.058	LRAT
Regulation of lipid metabolism by PPARalpha	1	15.7×	0.094	ABCB4
Disorders of transmembrane transporters	1	15.5×	0.094	ABCB4
Stimuli-sensing channels	1	15.1×	0.094	BEST1

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
photoreceptor cell maintenance	6	153.7×	1e-10	ABCA4, RHO, SPATA7, CRB1, LCA5, BBS1
visual perception	8	45.4×	1e-10	CNGB3, ABCA4, RHO, RPE65, BEST1, SPATA7, LRAT, BBS1
detection of light stimulus involved in visual perception	3	138.9×	6e-05	RPE65, BEST1, CRB1
retinoid metabolic process	3	106.2×	1e-04	ABCA4, RPE65, LRAT
vitamin A metabolic process	2	343.9×	4e-04	RPE65, LRAT
gene expression	4	22.8×	6e-04	RHO, CRB1, MFSD8, LRP5
phototransduction, visible light	2	185.2×	0.001	ABCA4, RHO
cellular response to light stimulus	2	150.5×	0.002	RHO, CRB1
retinal metabolic process	2	133.8×	0.002	ABCA4, RPE65
microtubule cytoskeleton organization	3	26.0×	0.003	RHO, SPATA7, BBS1
phospholipid translocation	2	89.2×	0.003	ABCA4, ABCB4
maintenance of location	1	1203.7×	0.009	MFSD8
camera-type eye photoreceptor cell development	1	1203.7×	0.009	CRB1
zeaxanthin biosynthetic process	1	1203.7×	0.009	RPE65
protein localization to photoreceptor connecting cilium	1	1203.7×	0.009	SPATA7
glycolipid metabolic process	1	601.9×	0.011	MFSD8
positive regulation of lipid transport	1	601.9×	0.011	LRAT
thermotaxis	1	601.9×	0.011	RHO
post-embryonic retina morphogenesis in camera-type eye	1	601.9×	0.011	CRB1
gamma-aminobutyric acid secretion, neurotransmission	1	601.9×	0.011	BEST1
inclusion body assembly	1	601.9×	0.011	MFSD8
response to fenofibrate	1	601.9×	0.011	ABCB4
rod bipolar cell differentiation	1	601.9×	0.011	RHO
retina development in camera-type eye	2	36.5×	0.011	MFSD8, BBS1
phospholipid transfer to membrane	1	401.2×	0.014	ABCA4
detection of temperature stimulus involved in thermoception	1	401.2×	0.014	RHO
cell-cell signaling involved in mammary gland development	1	401.2×	0.014	LRP5
establishment of bipolar cell polarity involved in cell morphogenesis	1	401.2×	0.014	CRB1
regulation of lysosomal protein catabolic process	1	401.2×	0.014	MFSD8
transmembrane transport	2	24.1×	0.016	ABCA4, ABCB4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 12

Druggability breadth: 5 of 14 evidence-associated genes (36%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRAT	1	3
ABCB4	1	2
CNGB3	0	0
ABCA4	0	0
RPE65	0	0
SPATA7	0	0
LCA5	0	0
RHO	0	0
BEST1	0	0
CAPN5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FRAMYCETIN	3	LRAT
BMS-986020	2	ABCB4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
ABCB4	4	ADMET:3, Binding:1
LRAT	1	Binding:1
RHO	1	Binding:1
LRP5	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase
LRAT	2.3.1.135	phosphatidylcholine-retinol O-acyltransferase
CAPN5	3.4.22.B25

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

2 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)
FRAMYCETIN	3	LRAT
BMS-986020	2	ABCB4

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	2	LRAT, ABCB4
C	Druggable family + PDB, no drug	4	CNGB3, ABCA4, RHO, CAPN5
D	Druggable family + AlphaFold only, no drug	2	RPE65, MFSD8
E	Difficult family or no structure, no drug	6	SPATA7, LCA5, BEST1, CRB1, LRP5, BBS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RPE65	0	LRAT
SPATA7	0	LRAT
CNGB3	0	—
ABCA4	0	—
LCA5	0	—
RHO	1	—
BEST1	0	—
CAPN5	0	—
CRB1	0	—
MFSD8	0	—
LRP5	1	—
BBS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE1/PHASE2	3
PHASE3	1
PHASE2/PHASE3	1
PHASE2	1
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06388083	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Phase 2/3 Study to Evaluate the Efficacy and Safety of Tinlarebant in Subjects With Stargardt Disease
NCT05244304	PHASE3	COMPLETED	Phase 3, Randomized, Placebo-Controlled Study of Tinlarebant to Explore Safety and Efficacy in Adolescent Stargardt Disease
NCT06300476	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of a Single Subretinal Injection of JWK006 Gene Therapy in Subjects With Stargardt Disease(STGD1)
NCT06467344	PHASE1/PHASE2	RECRUITING	Study to Evaluate ACDN-01 in ABCA4-related Stargardt Retinopathy (STELLAR)
NCT07002398	PHASE1/PHASE2	RECRUITING	Safety and Preliminary Efficacy of VG801 in Patients With ABCA4 Mutation-associated Retinal Dystrophy (Stargardt Disease)
NCT04489511	PHASE2	COMPLETED	Study of STG-001 in Subjects With Stargardt Disease
NCT03772938	PHASE1	UNKNOWN	Stem Cells Therapy in Degenerative Diseases of the Retina
NCT07063251	EARLY_PHASE1	RECRUITING	An Clinical Study Evaluating the Safety, Tolerability, and efficAcy of HG005 in StaRgardT Disease
NCT05674058	Not specified	ACTIVE_NOT_RECRUITING	Function and Imaging Assessments for G1961E-associated Stargardt Disease
NCT06435000	Not specified	RECRUITING	An Observational Study in Subjects to Follow the Progression of Stargardt Disease Type 1 (STGD1) Caused by Bi-Allelic Autosomal Recessive Mutations in the ABCA4 Gene
NCT06445322	Not specified	RECRUITING	Prescreening Study to Identify Potential Stargardt Participants for ACDN-01 Clinical Trials (STARPATH)
NCT03297515	Not specified	COMPLETED	Therapeutic Potential of Omega-3 Fatty Acids Supplementation in Dry Macular Degeneration and Stargardt Disease
NCT04281732	Not specified	UNKNOWN	Visual Performance Measures in a Virtual Reality Environment for Assessing Clinical Trial Outcomes in Those With Severely Reduced Vision
NCT05258032	Not specified	UNKNOWN	Structural and Functional Characterization of Rare Ocular Diseases

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TINLAREBANT	3	2
STG-001	2	1