Genotype-Phenotype Correlations in Denys-Drash Syndrome in Children

Area of Science:

• Genetics
• Pediatric Nephrology
• Oncology

Background:

• Denys-Drash syndrome (DDS) is a rare genetic disorder characterized by nephrotic syndrome (NS), Wilms tumor (WT) susceptibility, and genitourinary defects.
• DDS is caused by pathogenic variants in the Wilms' tumor suppressor gene (WT1), predominantly in exons 8 and 9.

Purpose of the Study:

• To investigate long-term clinical outcomes in children with Denys-Drash syndrome.
• To establish genotype-to-phenotype correlations based on WT1 exon variant localization.

Main Methods:

• A retrospective national study was conducted in France from 2000 to 2022.
• Identified children with pathogenic WT1 variants in exons 8 or 9.

Main Results:

• Fifty-eight children with DDS were analyzed, with 23 having exon 8 variants and 35 having exon 9 variants.
• Children with exon 8 variants exhibited earlier onset of NS (median 0.3 years) and kidney failure (median 0.3 years) compared to exon 9 variants (NS: median 1.4 years, KF: median 1.4 years).
• Exon 9 variants were significantly associated with WT development (P < 0.0015), with over 90% of truncating variants located in exon 9.

Conclusions:

• Clinical outcomes in DDS are significantly influenced by the exon localization of WT1 variants.
• Understanding these genetic risks is crucial for personalized patient care, especially with advancements in genomic newborn screening.