Loss-of-function Variants in <i>CPT1C</i> : No Support for a Causal Role in Hereditary Spastic Paraplegia
Bibliographic record
Abstract
ABSTRACT Background Hereditary spastic paraplegias (HSPs) are neurodegenerative disorders characterized by lower limb spasticity. Pathogenic variants in CPT1C have been implicated in HSP. Objective To assess if CPT1C loss-of-function (LOF) variants are causally associated with HSP. Methods We analyzed whole-genome sequencing (WGS) data from UK Biobank (UKBB), whole-exome sequencing (WES) data from a Canadian cohort of HSP (Can-HSP), and genetic data from the GENESIS cohort—a large international cohort of patients with rare hereditary diseases, including HSP. Results Among >170 CPT1C LOF carriers in the UKBB (n=150,119), none exhibited HSP phenotypes. Among 585 HSP patients from Can-HSP, we did not find patients with CPT1C LOF variants. In the GENESIS cohort (n=21,217), three individuals carrying CPT1C LOF variants were also diagnosed with HSP; however, all three also carry pathogenic variants in established HSP-associated genes. Conclusion Our study does not support a causal role for CPT1C LOF variants in HSP.
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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 | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 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".