EHMT2 LOSS-OF-FUNCTION ALTERATIONS CAUSE A KLEEFSTRA-LIKE SYNDROME
Bibliographic record
Abstract
ABSTRACT Dysregulation of the epigenetic machinery is associated with neurodevelopmental defects in humans. Kleefstra syndrome (KS) is a neurodevelopmental syndrome caused by heterozygous alterations in the gene EHMT1 that cause loss-of-function. EHTM1 and EHMT2 are highly similar histone methyltransferases that play relevant roles in development. Despite their similarity, individuals with alterations in EHMT2 have never been described. Here, we describe a pediatric patient with a KS-overlapping phenotype and a single base de novo substitution in EHMT2 that causes the amino acid change p.Ala1077Ser in the catalytic SET domain. This change causes a reduction in the affinity of the catalytic domain for the H3 tail and in the activity of the enzyme by three- to five-fold. DNA methylation, histone methylation and gene expression profiles suggest a significant overlap between the EHMT2 p.Ala1077Ser variant and KS. Based on this evidence we suggest that EHMT2 haploinsufficiency causes a Kleefstra-like syndrome. Although we cannot rule out dominant negative effects caused by the EHMT2 p.Ala1077Ser variant, our data and previously published data suggest that loss of EHMT2 function is probably more detrimental to cells than loss of EHMT1, explaining why individuals with alterations in EHMT2 are very rare.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".