| WT1 variant class | Cohort size | Wilms tumor | CKD | Age / noteworthy phenotype | Methodological caution |
|---|---:|---:|---:|---|---|
| Truncating | 19 | 18/19 (95%) | 5/19 (26%) | Wilms tumor was commonly the first manifestation; 4/5 CKD cases followed Wilms-tumor treatment. Bilateral tumors occurred frequently in this class. (pqac-00000023, pqac-00000024) | **18/19 is an observed cohort proportion, not lifetime penetrance.** The cohort was clinically ascertained and relatively young; later CKD may be undercounted. Prior nephrectomy and prophylactic or therapeutic renal ablation create competing risks that complicate tumor-penetrance estimation. (pqac-00000011, pqac-00000022, pqac-00000025) |
| Exon or multiexon deletion | 4 | 4/4 (100%) | 1/4 (25%) | All four had Wilms tumor; one deletion carrier developed gonadoblastoma at age 8 months. (pqac-00000022, pqac-00000023, pqac-00000024) | Very small subgroup; 4/4 must not be interpreted as a precise lifetime-risk estimate. Copy-number variants may also have been underdetected by historical testing methods. (pqac-00000019, pqac-00000022) |
| Missense | 13 | 2/13 (15%) | 13/13 (100%) | Median CKD onset was 2 months. Diffuse mesangial sclerosis was confined to missense carriers in this cohort; DNA-binding-region missense variants are associated with the earliest, fastest-progressing nephropathy. (pqac-00000023, pqac-00000024, pqac-00000011) | Five patients with missense or splice variants underwent bilateral nephrectomy before age 7 and therefore could no longer develop renal tumors, lowering observable tumor occurrence. Variant-position effects within exons 8–9 further limit class-wide generalization. (pqac-00000023, pqac-00000025) |
| Intron 9 splice-site | 4 | 0/4 (0%) | 4/4 (100%) | Median CKD onset was 15 years; this class typically produces later, slower glomerulopathy and has low Wilms-tumor risk (≤3% in aggregated evidence), while gonadal dysgenesis and gonadoblastoma risk are comparatively prominent. (pqac-00000023, pqac-00000011) | Zero tumors among four carriers does **not** establish zero lifetime risk. Small sample size, age-dependent expression, renal ablation, and ascertainment constrain inference. (pqac-00000011, pqac-00000023) |
| Other splice-site variants | 3 | 2/3 (67%) | 2/3 (67%) | Median CKD onset among affected individuals was 6 months. These variants produce aberrant or nonfunctional WT1 protein rather than altering the +KTS:−KTS ratio characteristic of intron 9 variants. (pqac-00000023) | Extremely small and molecularly heterogeneous subgroup spanning introns 6–8; proportions should not be treated as stable penetrance estimates. (pqac-00000023) |
| **All splice-site variants** | **7** | **2/7 (29%)** | **6/7 (86%)** | Both Wilms tumors occurred in the non-intron-9 subgroup; no tumor occurred among the four intron-9 carriers. (pqac-00000022, pqac-00000023) | Pooling intron-9 and other splice variants obscures mechanistically and clinically distinct classes. (pqac-00000023) |


*Table: Variant-stratified Wilms tumor and chronic kidney disease observations from the 2024 Dutch national WT1 cohort, contextualized with GeneReviews. The observed proportions are not equivalent to lifetime penetrance because of clinical ascertainment, limited follow-up, small subgroups, and competing risk from renal ablation.*