biostudies-literatureUnknown66(12)Van Vooren E<h4>Purpose</h4>Recessive RPE65-associated retinopathy is a well-known target for gene therapy, whereas dominant RPE65-associated retinopathy, due to the Irish founder variant p.(D477G), has been reported only once until now and is very rare. Here, we present the discovery of a novel, second dominant RPE65-associated retinopathy caused by variant c.1555G>A, p.(E519K).<h4>Methods</h4>Genomic data was investigated in a Belgian discovery cohort (n = 2873) and an international replication cohort (n = 18,796) with inherited retinal disease (IRD). Heterozygous p.(E519K) individuals underwent extensive phenotyping. Haplotype phasing was based on long-read sequencing and microsatellite analysis. Variant p.(E519K) was assessed in vitro using an enzymatic assay, Western blotting, co-immunoprecipitatInvestigative ophthalmology & visual science53https://www.ebi.ac.uk/biostudies/studies/S-EPMC12468096biostudies-literatureRPE65 Variant p.(E519K) Causes a Novel Dominant Adult-Onset Maculopathy in 83 Affected Individuals.PMC12468096Smirnov VTuupanen SPostelmans LDemaret TDe Bruyne MDominant RPE65-p.(E519K) ConsortiumVan Heetvelde MVan Vooren EVan Os LJacob JSheri NHoefsloot LDahan KStephenson KAJRedmond TMUppal SGonzalez AILeroy BPDhaenens CMVermeer SGeens EVan de Sompele SMaystadt IRasquin FMahieu QRuys JGregory-Evans CYDe Baere EKohl SGregory-Evans KBauwens MVan Den Broeck FPoliakov EThiadens AAHJZuleger TDe Zaeytijd JPlatteau EMacDonald IMfalseRPE65 Variant p.(E519K) Causes a Novel Dominant Adult-Onset Maculopathy in 83 Affected Individuals.<h4>Purpose</h4>Recessive RPE65-associated retinopathy is a well-known target for gene therapy, whereas dominant RPE65-associated retinopathy, due to the Irish founder variant p.(D477G), has been reported only once until now and is very rare. Here, we present the discovery of a novel, second dominant RPE65-associated retinopathy caused by variant c.1555G>A, p.(E519K).<h4>Methods</h4>Genomic data was investigated in a Belgian discovery cohort (n = 2873) and an international replication cohort (n = 18,796) with inherited retinal disease (IRD). Heterozygous p.(E519K) individuals underwent extensive phenotyping. Haplotype phasing was based on long-read sequencing and microsatellite analysis. Variant p.(E519K) was assessed in vitro using an enzymatic assay, Western blotting, co-immunoprecipitat2025-01-01T00:00:00Z2025 Sep2026-07-15T06:03:08.136Z2026-06-30T03:16:36.389ZS-EPMC124680964098579910.1167/iovs.66.12.53