Functional analysis of human EED variants using <i>Drosophila</i>
Bibliographic record
Abstract
The Polycomb Repressive Complex 2 is an epigenetic reader/writer that methylates histone H3K27. Rare germline partial loss-of-function (pLoF) variants in core members of the complex (EZH2, EED, and SUZ12) cause overgrowth and intellectual disability syndromes, whereas somatic variants are implicated in cancer. However, up to 1% of the general population will have a rare variant in one of these genes, most of which would be classified as variants of uncertain significance (VUS). Towards screening these VUS for partial LoF alleles that may contribute to disease, here we report functional assays in Drosophila to interrogate Embryonic Ectoderm Development (EED) missense variants. We mimicked the amino acid change(s) of EED variants into its Drosophila ortholog, esc, and tested their function. Known likely benign variants functioned wildtype and known pathogenic variants were LoF. We further demonstrate the utility of this calibrated assay as a scalable approach to assist clinical interpretation of human EED VUS.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| 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".