Genotype-Phenotype Associations in Patients with Congenital and Infantile Nephrotic Syndrome
Bibliographic record
Abstract
Background: Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are disorders of the slit diaphragm of podocytes in the glomerular basement membrane. CNS manifests during the first three months of life, and INS between 3-12 months. The clinical features of the diseases include nephrotic-range proteinuria, hypoalbuminemia, and edema. The most common causes of CNS and INS are mutations in the NPHS1 and NPHS2 genes encoding nephrin and podocin, respectively. This study aimed to establish specific genetic characteristics of CNS and INS and their clinical correlations in the North American population. Methods: Nine Pediatric Nephrology Research Consortium (PNRC) sites retrospectively reviewed charts of 36 patients born between 1998 and 2019 with CNS or INS and underwent genetic testing. ClinVar, SNP, and Human mutation database confirmed the mutation's pathogenicity. Results: NPHS1 mutations were more often seen in CNS patients (27/36; 75%), whereas the INS group had more frequent mutations of WT1 (3/11;27.2%) and NPHS2 (4/11;36.3%) genes. Among patients with NPHS1 mutations, the splice site had more mutations than the gene coding region, irrespective of the group. Among these mutations, IVS17-1 G>A splice mutation was found in 4 subjects that showed aggressive features of CNS. Interestingly, the mutation's pathogenicity was confirmed by ClinVar, SNP, and Human mutation database. In patients with CNS, the frequency (9/18;50%) of multiple mutations of the NPHS1 gene was higher than in the INS group (2/5;40%) and significantly associated with hyperproteinemia (p=0.021) and hypoalbuminemia (p=0.03). Albumin infusions were much more effective in CNS patients with NPHS2/WT1 mutations than those with NPHS1 mutations. In INS patients with WT1 mutations, albumin infusions were less effective in supporting serum albumin levels. Conclusions: Variations in splice sites, especially IVS17-1 G>A, and multiple mutations in the NPHS1 gene were associated with a more aggressive course of CNS in infants.
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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 | 0.002 |
| 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".