Exome Sequencing "Firsthand" for Polycystic Kidney Diseases: Impact beyond PKD1/PKD2 Identification on ADPKD Clinical Management
Bibliographic record
Abstract
Background: Genetic testing is currently considered non-mandatory for managing typical autosomal dominant polycystic kidney disease (ADPKD) patients. However, an increasing number of genes are associated with ADPKD. For atypical forms of ADPKD, the diagnostic yield may be lower with targeted genetic analysis. Genome-wide analysis can highlight incidental findings that could impact clinical management. Recent studies suggest that exome sequencing (ES) could be as efficient as standard methods, even for PKD1/PKD2 analysis. Methods: Among 3523 index cases undergoing ES genetic testing at Sorbonne University, Paris, France, 721 patients were categorized as having cystic diseases (149 with typical ADPKD and 572 with atypical ADPKD). We compared the diagnostic yield in both typical and atypical ADPKD. Then, we analyzed the rate of incidental findings impacting ADPKD clinical management (pathogenic variants not anticipated that explain part of the phenotype, or for which the patient is not/pre-symptomatic, or variants of interest in genetic counseling) among patients with a pathogenic variant in PKD1/PKD2 genes and compared this to the entire cystic nephropathy cohort. Results: Of the 721 patients with cystic nephropathy, 239 had a positive genetic test with a pathogenic or likely pathogenic variant (33%). The diagnosis rate was 59.1% for typical ADPKD patients compared to 26.4% in the atypical cystic nephropathy population. In the typical ADPKD group, PKD1 and PKD2 represented only 60.3% of pathogenic variants found by ES. Double hits represented 13.1% of patients with a positive genetic test, reaching 20.6% in the PKD1/PKD2 population. Conclusion: Our results showed a great diversity in genes responsible for adult’s cystic nephropathies, even in the typical ADPKD population. We observed a significant rate of incidental findings impacting clinical ADPKD management. Our work suggests that ES should be considered a first-tier test for any ADPKD patients to optimize their clinical management.Percentage of patients carrying a second variant in a second gene among patients with a positive genetic diagnosis.
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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 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".