RPE65 Variant p.(E519K) Causes a Novel Dominant Adult-Onset Maculopathy in 83 Affected Individuals
Bibliographic record
Abstract
Purpose: 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). Methods: 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-immunoprecipitation, cellular thermal shift assay (CETSA), minigene assays, and in silico using protein modeling (AlphaFold). Results: The monoallelic p.(E519K) variant was found in 83 affected individuals from Belgium, the Netherlands, France, and Canada, all of European ancestry. A shared region of 464 kilobases (kb) confirmed a founder effect. Variant p.(E519K) lowers RPE65 protein expression and enzymatic activity, with altered protein stability predicted and experimentally confirmed. Genotype-phenotype data support dominant inheritance and phenotypic variability, respectively, characterized by late-onset macular dystrophy with two main subtypes. Conclusions: The discovery of a dominant RPE65-IRD due to founder variant p.(E519K) reduces the diagnostic gap in dominant IRD and highlights a novel target for therapy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.000 | 0.003 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".