De novo missense variants in <scp> <i>BAIAP2</i> </scp> are associated with developmental and epileptic encephalopathies
Bibliographic record
Abstract
OBJECTIVE: Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) plays a crucial role in dendritic spine morphogenesis and excitatory synapse formation. We establish de novo variants in BAIAP2 as a novel genetic cause for developmental and epileptic encephalopathies (DEEs). METHODS: Using whole exome/genome sequencing, we identified de novo missense variants in BAIAP2 in six patients with DEEs. Molecular docking was utilized to predict the effect of these variants on the protein structures. Functional assays were conducted by overexpressing wild-type and mutant BAIAP2 in cultured cells, primary hippocampal neurons, and zebrafish. RESULTS: All six patients exhibited severe infantile or early childhood onset epilepsy, with refractory seizures in four individuals. Language and motor development delays were prevalent, with varying degrees of intellectual disability observed. The missense variants were clustered within the multiple phosphorylation site region that is critical for the autoinhibited conformation of BAIAP2 through 14-3-3 binding. In silico modeling and HeLa cell spreading assays demonstrated that BAIAP2 mutants potentially disrupted its autoinhibited state and induced hybrid filopodia-lamellipodia protrusions in cells, phenocopying the effects of Rac1/Cdc42 overexpression. Electrophysiological recordings revealed that neurons expressing BAIAP2 variants exhibited increased excitability, due to enhanced excitatory synaptogenesis. Additionally, transgenic overexpression of mutant BAIAP2 mRNA in zebrafish embryos led to developmental defects, abnormal neurite growth, and enhanced sensitivity to pentylenetetrazole-induced locomotor hyperactivity. SIGNIFICANCE: De novo variants in BAIAP2 represent a novel cause of DEEs. The functional consequences of these variants suggest that the gain of function of BAIAP2 can affect filopodia-lamellipodia formation, dendritic spine development, and synaptic transmission.
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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 | 0.001 |
| 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".