Comparative Whole-Exome Sequencing in Patients with Loin Pain Hematuria Syndrome and Isolated Hematuria
Bibliographic record
Abstract
Background: Loin pain hematuria syndrome (LPHS) is an ultrarare disease characterized by unexplained chronic loin pain and hematuria, with no identifiable urological causes. Objectives: To investigate the genetic factors contributing to hematuria and pain in patients with LPHS and isolated hematuria (IH) using whole exome sequencing (WES). Methods: In this single-center study, 17 consecutive patients with LPHS and 10 with IH underwent WES from Jan 2022-Jan2023. Bioinformatically created hematuria (n=130) and pain (n=577) gene panels were evaluated. Variant annotation, interpretation, and prioritization were performed using the Franklin platform. Results: A total of 44 variants were identified in 35 hematuria genes.17 and 27 variants were found in 8 IH patients and 16 LPHS patients. In 3 LPHS patients, we detected 3 pathogenic/likely pathogenic (P/LP) missense variants in COL4A4 (c.G3044A:p.Gly1015Glu), ABCA1 (c.2861C>T: p.Ser954Leu)exacerbating glomerular endothelial cell injury by promoting cholesterol accumulation and CXCR4 (c.373C>G: p.Leu125Val) inducing podocyte injury. In another 2 IH patients, we found a missense variant in COL4A5 (c.T4561A:p.Cys1521Ser)and a frameshift deletion in COL4A3 (c.4329_4330del:p.Gly1445Lfs*64). A total of 34 variants of uncertain significance (VUS), including genes affecting podocytes (FAT1, ITGB3, ITGB4, COQ2, APOA1, and GAPVD1), GBM (GPC5, COL4A5), and endothelial cells (CFH, PLG) were also identified. A total of 18 rare variants were found in 17 pain genes unique to LPHS. None of these pain variants were P/LP. Conclusion: The etiology of hematuria in LPHS displays both genic and allelic heterogeneity. As expected, variants in Type IV Collagen genes (COL4A3-5) were pathogenic, caused hematuria, and were identified in IH and LPHS patients. Many VUS were identified in patients with isolated hematuria and LPHS. To our knowledge, this is the first WES report on LPHS patients globally.Pathogenic or likely pathogenic variants in hematuria genes identified in this study
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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 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".