CUL1 variants cause severe neurodevelopmental disorders: Insights from human genetics and a zebrafish model of microcephaly
Bibliographic record
Abstract
Microcephaly is a neurodevelopmental anomaly characterized by reduced head circumference and impaired brain growth, often accompanied by intellectual disability (ID), developmental delays, and seizures. While numerous genes have been implicated in microcephaly, the role of the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex, particularly its core component CUL1, remains poorly understood. In this study, we identified heterozygous de novo and inherited variants in the CUL1 gene in four unrelated families with severe microcephaly, ID, and developmental delays. To investigate the functional consequences of CUL1 loss of function, we developed a zebrafish model with knockdown of cul1a&b, which exhibited significant reductions in central nervous system size and behavioral defects, mirroring the clinical phenotypes observed in patients. These findings establish CUL1 as a novel gene associated with severe neurodevelopmental disorders (NDDs) and highlight its critical role in brain development. Our study provides genotype-phenotype correlations for CUL1 in NDDs, expanding the genetic spectrum of disorders linked to the SCF complex and underscoring its importance in neurodevelopment.
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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".