Detection of SQSTM1/P392L post-zygotic mutations in Paget’s disease of bone
Bibliographic record
Abstract
Paget's disease of bone (PDB) is transmitted, in one-third of cases, in an autosomal dominant mode of inheritance with incomplete penetrance. The SQSTM1/P392L germinal mutation is the most common mutation associated with PDB. Given the focal nature of PDB, one team of investigators showed that SQSTM1/P392L somatic mutations could occur in pagetic bone lesions in the absence of germinal mutations detectable in the peripheral blood. The objectives of this study were to develop a reliable method to detect SQSTM1/P392L post-zygotic mutations, by optimizing a polymerase chain reaction (PCR)-clamping method reported to be effective in detecting post-zygotic mutations in peripheral blood from patients with fibrous dysplasia; and to evaluate the frequency of this post-zygotic mutation in PDB patients. We used a locked nucleic acid (LNA) specifically designed for the SQSTM1/P392L mutation, which blocks the wild-type allele amplification during the PCR. DNA from 376 pagetic patients and 297 controls, all without any SQSTM1/P392L germinal mutation, was analyzed. We found that 4.8 % of PDB patients and 1.4 % of controls were carriers of this post-zygotic mutation [p = 0.013, OR 3.68 (1.23; 11.00)]. PDB patient carriers of a post-zygotic mutation had a lower number of affected bones and Renier's index than patients carrying a germinal mutation, suggesting a lower disease extension. We also demonstrated that this post-zygotic mutation was restricted to the monocytic lineage. These results confirmed that LNA PCR clamping is effective for the detection of SQSTM1/P392L post-zygotic mutations, which may occur in patients with PDB.
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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".