| Phenotype (plain language) | Phenotype type | Typical onset | Progression | Frequency/notes with quantitative values when available | Suggested HPO term(s) |
|---|---|---|---|---|---|
| Severe visual impairment / low visual acuity | Symptom/sign | Birth, infancy, or early childhood; mean self-reported symptom onset 2.2 ± 2.1 years in one natural-history cohort | Usually progressive, though acuity decline may be slow early; median age to low vision 33.8 years and blindness 41.4 years by BCVA in Italian cohort (pqac-00000020, pqac-00000017, pqac-00000018) | Reported in 32/43 (74.4%) in Italian cohort; phase/phenotype labels include LCA and EOSRD; BCVA often severely reduced, but some residual vision may persist into adulthood (pqac-00000020, pqac-00000007, pqac-00000005) | HP:0000505 Visual impairment; HP:0000518 Cataract not primary; HP:0000572 Reduced visual acuity |
| Night blindness / severe nyctalopia | Symptom | Early childhood to infancy; often among earliest symptoms | Progressive, reflecting early rod dysfunction | Reported in 28/43 (65.1%) in Italian cohort; described as a characteristic early feature across RPE65 disease and often severe (pqac-00000020, pqac-00000001, pqac-00000002) | HP:0000662 Nyctalopia |
| Nystagmus / roving eye movements | Sign | Congenital or infancy | Often persistent; may accompany severe early vision loss | Reported in 24/43 (55.8%) in Italian cohort; classic early LCA/EOSRD sign noted in foundational reviews (pqac-00000020, pqac-00000005, pqac-00000007) | HP:0000639 Nystagmus |
| Constricted peripheral visual fields / visual field loss | Symptom/test | Childhood to adolescence, sometimes recognized later than nyctalopia | Progressive constriction | Reported in 18/43 (41.9%) in Italian cohort; Korean/Testa reviews describe progressive visual field constriction as a core feature; pivotal VN studies also used residual field as part of viability/eligibility assessment (pqac-00000020, pqac-00000001, pqac-00000002, pqac-00000006) | HP:0001133 Constricted visual field |
| Poor pupillary light responses / abnormal pupils | Sign | Infancy | Usually persistent | Classic LCA/EOSRD feature in broader review literature; often accompanies severe congenital/early visual dysfunction (pqac-00000005, pqac-00000007) | HP:0000613 Photophobia overlaps; HP:0007690 Abnormal pupillary light reflex |
| Photophobia / photoaversion | Symptom | Childhood | Variable; may persist | Reported in 20/43 (46.5%) in Italian cohort; also included among variable LCA manifestations in review literature (pqac-00000020, pqac-00000008) | HP:0000613 Photophobia |
| Markedly reduced or absent ERG | Test abnormality | Detectable at diagnostic testing in infancy/childhood | Typically severe and persistent; reflects generalized rod-cone dysfunction | ERG undetectable in 26/34 (76.5%) in Italian cohort; Kumaran review describes ERG as typically undetectable or severely abnormal in LCA/EOSRD; Testa 2024 notes reduced/non-detectable ERG as typical in RPE65 disease (pqac-00000017, pqac-00000018, pqac-00000005, pqac-00000002) | HP:0030533 Abnormal electroretinogram; HP:0000550 Reduced retinal function |
| Minimal or normal early fundus, later retinal degeneration | Sign/imaging | Early childhood may have minimal abnormalities; later childhood/adulthood show degeneration | Progressive | Early fundus may be normal/minimally abnormal; later findings can include vessel attenuation, disc pallor, peripheral pigmentary change, salt-and-pepper change, or RP-like fundus (pqac-00000001, pqac-00000005, pqac-00000019, pqac-00000007) | HP:0000520 Prolonged dark adaptation not fundus; HP:0001103 Abnormality of the retina; HP:0000548 Retinal degeneration |
| Reduced/absent fundus autofluorescence | Imaging finding | Childhood to adulthood when imaged | Usually reflects progressive retinal/RPE dysfunction | Testa 2024 review describes markedly reduced/absent FAF as typical; useful in structural assessment and treatment selection (pqac-00000002) | HP:0030610 Abnormal fundus autofluorescence |
| Retinal thinning / reduced central foveal thickness | Imaging finding | Usually documented from childhood onward | Progressive overall; cross-sectional decline with age | Central foveal thickness declined at about −0.6%/year cross-sectionally in Italian natural history study; ONL thinning common (~79% of eyes in excerpted analysis) (pqac-00000017, pqac-00000018) | HP:0030829 Retinal thinning; HP:0000546 Retinal atrophy |
| Epiretinal membrane | Imaging/sign | Later childhood to adulthood | Variable | Seen in 5/31 (16.1%) on OCT in Italian cohort; secondary rather than defining phenotype (pqac-00000017) | HP:0011505 Epiretinal membrane |
| Oculodigital sign / eye-poking behavior | Behavioral sign | Infancy/early childhood | Can persist | Classic LCA/EOSRD feature emphasized in foundational review, though not quantified in RPE65-specific natural-history excerpt (pqac-00000005) | HP:0000657 Oculodigital sign |


*Table: This table summarizes the main clinical phenotypes reported for RPE65-related retinopathy, including onset, progression, and quantitative natural-history details where available. It is useful for structuring phenotype annotations and mapping them to HPO terms.*