Introduction: Denys-Drash syndrome (DDS) is a rare disease typically associated with a triad of early onset nephrotic syndromes (NS), susceptibility to Wilms tumor (WT), and genitourinary structural defects. DDS is caused by Wilms’ tumor suppression gene (WT1) variants, with the most frequent variants in exons 8 and 9. This study aimed to evaluate the long-term clinical outcomes and genotype-to-phenotype correlations in a large, multicenter cohort of children with typical DDS. Methods: We conducted a national retrospective study of all children diagnosed with a pathogenic variant in WT1 exons 8 or 9 in France between 2000 and 2022. Results: Fifty-eight children with DDS and variants in exons 8 (n = 23) and 9 (n = 35) of the WT1 gene were identified. Half of the children presented with NS (57% congenital, median age at presentation 0.3 years [interquartile range, IQR: 0.0–0.6]). Twenty-nine percent of children developed WT at a median age of 1.2 (0.5–2.2) years. Children with a variant in exon 8 developed NS much earlier than those with a variant in exon 9 (P = 0.0048), regardless of the type of genetic variation, leading to earlyier kidney failure (KF) (0.3 vs.1.4 years respectively; P = 0.0001) and higher mortality (35% vs 9%, P = 0.02). More than 90% of the truncating variants were located in exon 9 and were significantly associated with the occurrence of WT compared with the DNA-binding-site variants (P < 0.0015). Conclusion: In our cohort, children's DDS clinical trajectory was associated with exon localization. In the era of genomic newborn screening, depicting genetic risk is of utmost importance for personalized patient care. © 2025 International Society of Nephrology< Leer menos