WT1 – Denys-Drash Syndrome

Denys-Drash syndrome (DDS) is an autosomal dominant disorder caused by heterozygous mutations in the Wilms tumor suppressor gene WT1. Patients present in infancy with diffuse mesangial sclerosis leading to rapid renal insufficiency, 46,XY disorder of sex development (male pseudohermaphroditism, hypospadias), and a high risk of Wilms tumor (nephroblastoma).

Clinical Validity

Definitive: Over 100 unrelated DDS probands with constitutional WT1 variants have been reported, predominantly de novo missense mutations in zinc-finger exons 8 and 9 and intron 9 splice-site changes, with familial segregation and functional concordance ([PMID:1655284]). Over 90% of DDS patients carry intragenic WT1 mutations, confirming a direct causal role ([PMID:9090524]).

Genetic Evidence

Inheritance is autosomal dominant with de novo occurrence in nearly all cases. Segregation has been documented in at least two multiplex families with paternal transmission of exon 9 mutations. A spectrum of >50 variants includes:

• Missense variants in ZF2/ZF3 (e.g., c.1180C>T (p.Arg394Cys))
• Intron 9 splice-site changes (e.g., c.1447+4C>T)
• Nonsense and frameshift alleles truncating zinc-finger domains Genetic evidence reaches a Strong level per ClinGen: multiple independent de novo probands, segregation, and variant classes across functional domains ([PMID:1655284], [PMID:9090524]).

Functional Evidence

WT1 mutations act via a dominant-negative mechanism or haploinsufficiency. Missense alleles in the zinc fingers reduce DNA-binding affinity and sequence selectivity; SAAB assays showed 1.4–14-fold decreased binding of DDS mutants ([PMID:8810912]). Dominant-negative effects via self-association of N-terminal domains have been demonstrated in vitro ([PMID:8388765]). WT1 isoforms regulate key developmental targets (EGFR suppression in glomerular epithelium; SRY and MIS promoter control), mirroring human renal and gonadal phenotypes ([PMID:9291179], [PMID:9815658]). Functional evidence is Strong.

Integration & Clinical Utility

WT1 testing is mandatory in infants with early nephrotic syndrome, 46,XY DSD or Wilms tumor risk. Molecular confirmation drives surveillance for renal failure and tumor prophylaxis, informs gonadectomy decisions, and enables genetic counseling. Clinically, early diagnosis allows for tailored nephrectomy and transplant timing to mitigate Wilms tumor risk.

Key Take-home: Constitutional WT1 mutations are definitively linked to Denys-Drash syndrome; early genetic testing guides renal, oncologic, and gonadal management.

References

• Cell • 1991 • Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. PMID:1655284
• Human mutation • 1997 • A clinical overview of WT1 gene mutations. PMID:9090524
• Biochemistry • 1996 • Effects of Denys-Drash syndrome point mutations on the DNA binding activity of the Wilms' tumor suppressor protein WT1. PMID:8810912
• Human molecular genetics • 1993 • Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. PMID:8388765
• Kidney international • 1997 • Regulation of renal EGF receptor expression is normal in Denys-Drash syndrome. PMID:9291179
• Clinical cancer research • 1997 • The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor. PMID:9815658

Evidence Based Scoring (AI generated)