WT1 Disorders

name: WT1_Disorders
display_name: WT1 Disorders
creation_date: "2026-09-01T00:00:00Z"
description: >-
  The WT1 disorders are the allelic series arising from constitutional lesions of
  WT1, the Wilms tumor 1 transcription factor required for both nephron and gonadal
  development. Because one gene serves two developmental programs, the members
  share a recognisable core of glomerulopathy, disordered gonadal development, and
  Wilms tumor risk, while differing in which of the three dominates and how early
  it arrives.
  What separates the members is the class of lesion, not the organ list. A zinc
  finger missense substitution acts as a dominant negative and gives the earliest
  and most severe glomerulopathy; an intron 9 splice donor variant shifts the +KTS
  isoform ratio without making a mutant protein and gives complete gonadal
  dysgenesis with later kidney failure; a contiguous 11p13 deletion removes one
  whole WT1 copy alongside PAX6 and gives haploinsufficiency plus aniridia. The
  grouping exists to hold that mechanistic contrast in one place while keeping the
  entries distinct.
  This grouping also carries a live nosological question. The GeneReviews WT1
  Disorder chapter has retired Denys-Drash and Frasier syndrome as clinical
  designations, describing one phenotypic continuum instead, but MONDO has no
  umbrella term for that continuum to bind. The grouping is how this knowledge base
  represents the continuum without either asserting a MONDO term that does not
  exist or collapsing entries whose mechanisms genuinely differ.
grouping_basis:
- SHARED_GENE_FAMILY
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared causal gene: every member is caused by a constitutional
  lesion of WT1, and the shared mechanism is disruption of the WT1 transcriptional
  program in the developing kidney and gonad. Members are kept as separate Disease
  entries rather than merged because the lesion classes are mechanistically
  distinct and are not interchangeable for prognosis or management: dominant
  negative zinc finger missense (Denys-Drash), whole gene deletion with
  haploinsufficiency and a contiguous gene syndrome (WAGR), and the WT1 associated
  malformation combination of Meacham syndrome. Splitting on lesion class rather
  than on organ involvement is what keeps the entries mechanistically coherent.
  Two boundary decisions are worth recording. Frasier syndrome (MONDO:0007635) is a
  member of this concept and is deliberately absent from the member list because it
  has no Disease entry yet; that is a curation gap, not an exclusion, and it is the
  most important addition this grouping is waiting on. Wilms Tumor
  (MONDO:0006058) is also excluded, on different grounds: it is the somatic tumor
  these syndromes predispose to rather than a constitutional WT1 disorder, and
  design decisions section 3a keeps germline predisposition syndromes separate from
  the tumors they predispose to.
membership_criteria:
- description: >-
    A disorder belongs to the WT1 disorders if it is caused by a constitutional
    lesion of WT1. Members characteristically show at least one of the WT1
    developmental consequences: a glomerulopathy, disordered gonadal development,
    or Wilms tumor predisposition.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_GENE
    description: A constitutional WT1 lesion is the cause of the disorder.
    gene:
      preferred_term: WT1
      term:
        id: hgnc:12796
        label: WT1
members:
- member: Denys-Drash Syndrome
  member_type: DISEASE
  display_name: Denys-Drash syndrome
  differentiating_mechanisms:
  - description: >-
      Heterozygous missense substitution in the WT1 zinc finger DNA binding domain,
      clustered in exons 8 and 9, acting as a dominant negative on the wild type
      protein. Distinguished within the group by diffuse mesangial sclerosis with
      kidney failure usually before age five, partial gonadal dysgenesis, and the
      highest Wilms tumor risk of the missense classes.
    gene:
      preferred_term: WT1
      term:
        id: hgnc:12796
        label: WT1
- member: WAGR Syndrome
  member_type: DISEASE
  display_name: WAGR syndrome
  differentiating_mechanisms:
  - description: >-
      Contiguous deletion at 11p13 removing one WT1 copy together with PAX6, so the
      WT1 lesion is haploinsufficiency rather than dominant negative interference.
      Distinguished within the group by aniridia, which is a PAX6 consequence and
      does not occur in the intragenic WT1 disorders, and by intellectual
      disability reflecting the wider deletion.
    gene:
      preferred_term: WT1
      term:
        id: hgnc:12796
        label: WT1
- member: Meacham syndrome
  member_type: DISEASE
  display_name: Meacham syndrome
  differentiating_mechanisms:
  - description: >-
      WT1 associated malformation syndrome distinguished within the group by
      congenital diaphragmatic and complex cardiac malformations with 46,XY
      disorder of sex development, in the relative absence of the prominent early
      nephropathy that defines Denys-Drash syndrome.
    gene:
      preferred_term: WT1
      term:
        id: hgnc:12796
        label: WT1
notes: >-
  Frasier syndrome (MONDO:0007635) is the outstanding member. Adding it would make
  this grouping the complete representation of the GeneReviews WT1 continuum and
  would let the dominant negative versus +KTS isoform imbalance contrast be read
  directly off two curated entries rather than out of the Denys-Drash entry's
  differential diagnoses block.