P.057 Next-generation sequencing to determine a genetic cause of familial intracranial aneurysms
Bibliographic record
Abstract
Background: Approximately 12-15% of patients with intracranial aneurysms (IA) have affected first-degree relatives, and are considered to have familial intracranial aneurysms (FIA). Individuals with FIA are at higher risk for aneurysm formation and subarachnoid hemorrhage. THSD1 is the only gene to be associated with nonsyndromic FIA at this time. Our study aims to find rare DNA variants that are major risk factors for FIA in our cohort of patients. Methods: To date we have enrolled 37 affected and 31 unaffected people from 16 families. We have done exome or genome sequencing on at least 1 person from each of 12 families. Results: A rare p.(R686W) variant in THSD1 was found in 1/12 families, but did not cosegregate fully with disease. While less attractive as the primary cause of FIA, we cannot rule out the potential modifying effects of THSD1 p.(R686W) in this family. A second candidate, an extracellular matrix gene within a chromosomal region previously implicated by familial mapping studies, contains rare variants in 4/12 of our families. All four variants are predicted to be damaging. Conclusions: Alongside environmental risk factors, individual FIA families may also have complex rare variant contributions to their disease, such as digenic and multi-locus contributions.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 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) | 0.006 | 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".