Families With Complex Genetics in the Extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease (eTGESP)
Bibliographic record
Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous and primarily due to mutations in PKD1 or PKD2. Complex inheritance with bilineal disease arising from two independently segregating PKD1, or PKD1 and PKD2 mutations have been reported in a small number of families. Here, we define the prevalence and clinical features of ADPKD families with complex genetics in 1,811 patients from 1,271 different families from eTGESP. Methods: All study patients underwent PKD1 and PKD2 mutation screening by targeted Next-Generation sequencing and multiplex ligation-dependent probe amplification in mutation-negative cases, as well as targeted NGS with a cystic disease panel of 50 genes. Standard algorithms for sequence alignment, base calling, and QC filtering were applied to identify rare (MAF ≤1%) deleterious variants of high and moderate impact as predicted by multiple predictive algorithms. Families with complex genetics were defined as those with two putative pathogenic mutations in PKD1, in PKD1 and PKD2, or in PKD1 or PKD2 with another non-PKD1 and non-PKD2 cystic disease mutation. Results: We found complex genetics in 71/993 (7.2%) of genetically resolved families. Among the families with complex genetics, 48 (68%) carried two PKD1 mutations, 5 (7%) carried both a PKD1 and PKD2 mutation, and 18 (25%) carried either a PKD1 or PKD2 mutation with a second mutation in other cystic disease genes (i.e. ALG8, ALG9, PKHD1, PRKCSH, SEC63, WFS1, and COL4A5). Analyses of phenotypegenotype correlations in these families are currently in progress. Conclusions: Gene locus and allelic heterogeneity have been shown to account for a significant proportion of disease variability in ADPKD. Here, we found complex genetics in 7% of a large cohort of families harboring two cystic disease mutations; the presence of a second mutation may potentially act as a modifier of the main effect mutation and contributes to the within-family disease variability.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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".