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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".