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. 2025 Jan 16;10(4):1205-1212.
doi: 10.1016/j.ekir.2025.01.014. eCollection 2025 Apr.

Genotype-Phenotype Correlations in Denys-Drash Syndrome in Children

Mathilde Glénisson  1   2 , Mathilde Grapin  3 , Thomas Blanc  1   2 , Evgenia Preka  3 , Julien Hogan  4 , Manon Aurelle  5   6   7 , Gwenaëlle Roussey  8 , Antoine Mouche  9 , Caroline Rousset-Rouviere  10 , Robert Novo  11 , Camille Faudeux  12 , Marc Fila  13 , Isabelle Vrillon  14 , Sylvie Cloarec  15 , Thomas Simon  16 , Jérôme Harambat  17 , Edouard Martinez Casado  18 , Julien Rod  19 , Morgane Carre Lecoindre  20 , Laurence Heidet  3   21 , Olivia Boyer  2   3   21 , Nicolas Garcelon  22   23 , Jessica Kachmar  20 , Guillaume Dorval  20 , Sabine Sarnacki  1   2
Affiliations

Genotype-Phenotype Correlations in Denys-Drash Syndrome in Children

Mathilde Glénisson et al. Kidney Int Rep. .

Erratum in

Abstract

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.

Keywords: Denys-drash syndrome; Nephrotic syndrome; WT1.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Alluvial diagram presenting the evolution of children with DDS. Children are depicted from their initial presentation (left) to their status at the last follow-up (right). DDS, Denys-Drash syndrome; WT, Wilms’ tumor.
Figure 2
Figure 2
Kaplan-Meier kidney survival estimates in patients with DDS based on exon or WT1 variant localization. (a) Without NS based on exon localization. (b) Without NS based on type of variant. (c) Non-WT1 variants based on exon localization. (d) Non-WT1 variants based on type of variant. P depending on log rank test. C2H2, Cis2-His2 variant; NS, nephrotic syndrome; WT, Wilms’ tumor.
See this image and copyright information in PMC

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