Variants in chondroitin sulfate metabolism genes in thrombotic storm
Bibliographic record
Abstract
INTRODUCTION: Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. MATERIAL AND METHODS: We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (<5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. RESULTS: We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). CONCLUSIONS: As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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 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".