Introduction & Objectives: Denys Drash syndrome (DDS) is caused by WT1 mutations and is associated with a high risk of Wilms tumour (WT) and diffuse mesangial sclerosis leading to end-stage renal disease (ESRD). Onset of disease is variable and there is a wide clinical spectrum with a genotype to phenotype correlation. In addition to the genetic alteration identified in patients, the surgical course greatly biases the assessment of progression to renal failure and the evaluation of the risk of further development of WT. In this work, we collected a large national cohort of patients with DDS and typical genotype in exon 8 or 9 of WT1 to determine the long-term progression and the influencing genetic and clinical factors playing a role in this clinical course. Materials & Methods: Multicentric retrospective analysis of children diagnosed with a mutation of WT1 in exon 8 or 9 in all the pediatric nephrological centres in France between 2000 and 2022. Results: 58 patients (25 males) with pathogenic variants in exon 8 (n=23) or 9 (n=35) of WT1 gene and clinical characteristics of DDS were identified during the study period in ten French pediatric nephrological centers. Patients were followed for a median of 8.3 years (IQR 5.2- 14.6). 32 patients (83% being females) presented with an early-onset nephrotic syndrome (NS) at a median age of 3 months (IQR 0.2-9.1). 17 patients (29%) developed a WT during the disease course. Abnormalities of external genitalia were diagnosed as the first clinical symptom in 20% of patients (n=12), at a median age of 6.4 months (IQR 0-11). Overall, 89% of patients developed ESRD at a median age of 0.8 years (IQR 0.3-1.6). Patients with variants in exon 8 developed ESRD statistically earlier than those with a variant in exon 9 (0.3 vs.1.4 years respectively; p=0.0001), with no correlation to either the type of variant or the protein domain affected. However, despite the earlier onset of ESRD in patients with exon 8 variants, age at kidney transplantation was identical in both groups of patients. Because of the earlier onset of NS in patients with exon 8 variants, the mortality rate was higher in these patients (p=0.02). Conclusions: We presented a large cohort of children with DDS with long-term evolution and identified a genotype to phenotype correlation linked to the position of the variant. Patients with variant in exon 8 developed earlier ESRD due to early-onset NS. This must be confirmedRead less <