<i>De novo</i> variants disrupt an <i>LDB1</i> -regulated transcriptional network in congenital ventriculomegaly
Bibliographic record
Abstract
Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is among the most common and least understood paediatric neurosurgical disorders. We have identified, in the largest assembled cerebral ventriculomegaly cohort (2697 parent-proband trios), an exome-wide significant enrichment of protein-altering de novo variants in LDB1 (P = 1.11 × 10-15). Eight unrelated patients with ventriculomegaly, developmental delay and dysmorphic features harboured loss-of-function de novo variants that truncate carboxy-terminal LIM interaction domain of LDB1, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest that LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through its binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging de novo variants in our cohort, with SMARCC1 (P = 5.83 × 10-9) and ARID1B (P = 1.80 × 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest that an LDB1-regulated transcriptional programme is essential for human brain morphogenesis.
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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 | 0.001 |
| 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".