👪

Inheritance

1

Autosomal dominant, usually de novo HP:0000006

Heterozygous WT1 zinc finger variants act dominantly. Most probands carry a de novo variant, though transmission from an affected or mosaic parent is documented.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:1655284 SUPPORT Human Clinical

"In two families analyzed, the mutations were shown to arise de novo."

Establishes the de novo origin typical of the syndrome.

PMID:32352694 SUPPORT Human Clinical

"WT1 disorder is inherited in an autosomal dominant manner."

GeneReviews states the mode of inheritance for the WT1 disorder spectrum.

PMID:32352694 SUPPORT Human Clinical

"in rare instances, a parent of an individual with WT1 disorder is heterozygous for the pathogenic variant identified in the proband"

Documents transmission from an affected parent, the first half of the inheritance claim.

+ 1 more reference

?

Discussions and Knowledge Gaps

1

Should Denys-Drash syndrome remain a distinct knowledge base entry, given that expert clinical practice has folded it into a WT1 disorder continuum?

KNOWLEDGE GAP OPEN wt1_continuum_vs_discrete_entity

Attached to

disease#Denys-Drash Syndrome

The GeneReviews WT1 Disorder chapter states that the Denys-Drash and Frasier designations are no longer clinically helpful and describes one phenotypic continuum. MONDO still carries separate terms, and there is no MONDO umbrella term for the continuum to bind, so the knowledge base cannot simply follow the clinical reframing. The mechanistic distinction is also real, a zinc finger missense dominant negative versus an intron 9 splice isoform imbalance, so collapsing the entries would lose a genuine mechanistic contrast. This entry is retained on that basis, with kb/groupings/WT1_Disorders.yaml carrying the continuum, and the question is recorded rather than silently resolved.

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful"

The GeneReviews statement that motivates this gap, quoted so the entry does not assert a nosology its own baseline source contradicts.

⚙

Pathophysiology

6

WT1 Zinc-Finger Missense Variant

A heterozygous constitutional point mutation in the WT1 zinc finger region, clustered in the exons encoding zinc fingers 2 and 3, alters the residues that make base specific contacts with target DNA.

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Heterozygous missense substitutions in the WT1 zinc finger DNA binding domain, clustered in exons 8 and 9, with a recurrent hot spot at zinc finger III. The phenotype requires an intact N terminal region alongside disrupted zinc finger function, which is the argument for dominant negative rather than haploinsufficient action.

WT1 sequence-specific DNA binding GO:0003700 ⇓ LOSS OF FUNCTION

Downstream

Biallelic WT1 Inactivation in Nephrogenic Rests The constitutional variant is the first hit; tumor initiation additionally requires a somatic event at the remaining allele.

Dominant-Negative Interference with WT1 Target Recognition

Show evidence (2 references)

PMID:1655284 SUPPORT Human Clinical

"In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found."

Establishes the heterozygous zinc-finger variant as the constitutional lesion.

PMID:8388765 SUPPORT Human Clinical

"The WT1 mutations in these patients are constitutional point mutations clustered in the zinc finger (ZF) encoding exons, particularly the exons encoding ZF2 and ZF3."

Localizes the variants to the zinc-finger 2 and 3 exons.

Dominant-Negative Interference with WT1 Target Recognition

The mutant protein retains its intact N terminal domain and interferes with the wild type WT1 present in the same cell, either by blocking its access to normal binding sites or by directing the complex to inappropriate ones. This is why the phenotype is more severe than that of a WT1 whole gene deletion.

Downstream

Loss of the WT1 Transcriptional Program in Podocytes

Failure of Gonadal Somatic Cell Differentiation

Show evidence (2 references)

PMID:8388765 SUPPORT Human Clinical

"we suggest that a dominant negative mechanism is at work here"

The primary report proposing dominant-negative action, on the argument that the phenotype requires an intact N-terminus alongside disrupted zinc-finger function.

PMID:9499425 SUPPORT Human Clinical

"A much more severe phenotype is seen in patients with Denys-Drash syndrome which results from heterozygous dominant-negative mutations of the gene."

Contrasts the dominant-negative mechanism here with the loss of the +KTS isoform in Frasier syndrome, where no mutant protein is made.

Loss of the WT1 Transcriptional Program in Podocytes

WT1 is required in the mature glomerulus, where it is highly expressed in podocytes and directs a transcriptional program governing podocyte differentiation and podocyte to mesangial cross talk. Its disruption is the proximate cellular lesion behind the glomerulopathy.

podocyte CL:0000653

glomerulus development GO:0032835 ↓ DECREASED

Animal models

Wt1 R394W knock-in mouse Mouse recapitulates The model reproduces the diffuse mesangial sclerosis nephropathy and was used to identify direct podocyte WT1 target genes by expression profiling and ChIP.

Downstream

Diffuse Mesangial Sclerosis

Show evidence (1 reference)

PMID:19797313 SUPPORT Model Organism

"By ChIP we show that Scel and Sulf1 are direct WT1 targets."

A diffuse mesangial sclerosis mouse line identifies direct podocyte WT1 target genes, substantiating a podocyte transcriptional program under WT1 control.

Failure of Gonadal Somatic Cell Differentiation

The same WT1 program is required for testicular somatic cell differentiation, so genotypic males show partial to complete gonadal dysgenesis with under virilization, and dysgenetic gonadal tissue carries gonadoblastoma risk.

sex differentiation GO:0007548 ↓ DECREASED

Downstream

Gonadal Dysgenesis

Ambiguous Genitalia

Gonadoblastoma Dysgenetic gonadal tissue is the substrate for gonadoblastoma, which is why prophylactic gonadectomy is offered.

Show evidence (1 reference)

PMID:1655284 SUPPORT Human Clinical

"Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development."

Links the WT1 lesion to urogenital developmental failure.

Diffuse Mesangial Sclerosis

The characteristic renal biopsy lesion, an expansion of mesangial matrix with podocyte hypertrophy progressing to global glomerular sclerosis. It is largely specific to WT1 disease among steroid resistant nephrotic syndrome cohorts and is the lesion that drives rapid progression to kidney failure.

glomerular mesangial cell CL:1000742

Downstream

Steroid-Resistant Nephrotic Syndrome

Proteinuria

Stage 5 Chronic Kidney Disease

Hypertension

Show evidence (2 references)

PMID:24402088 SUPPORT Human Clinical

"Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases."

Establishes diffuse mesangial sclerosis as the WT1-specific lesion against a 700-patient steroid-resistant nephrotic syndrome comparison cohort.

PMID:9607189 SUPPORT Human Clinical

"Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases."

Documents the biopsy lesion in a WT1-mutant early-onset nephrotic syndrome series.

Biallelic WT1 Inactivation in Nephrogenic Rests

A somatic second hit at the remaining WT1 allele within persisting nephrogenic rests completes tumor suppressor inactivation and initiates Wilms tumor, the classical two hit sequence acting on a constitutional first hit.

Genetic context variant_origin: SOMATIC zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Reduction to homozygosity for the mutant WT1 allele within tumor tissue, observed as loss of the wild type allele.

Downstream

Nephroblastoma

Show evidence (1 reference)

PMID:1655284 SUPPORT Human Clinical

"Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele."

Demonstrates loss of the wild-type allele in the tumors themselves, which is the somatic second hit this node asserts.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

9

Cardiovascular 1

Hypertension HP:0000822

Show evidence (1 reference)

PMID:24402088 SUPPORT Human Clinical

"WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression."

Reports hypertension at presentation as more frequent in WT1 disease.

Genitourinary 8

Steroid-Resistant Nephrotic Syndrome VERY_FREQUENT HP:0012588

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy."

GeneReviews names steroid-resistant nephrotic syndrome as the defining renal phenotype.

Diffuse Mesangial Sclerosis FREQUENT HP:0001967

Show evidence (2 references)

PMID:24402088 SUPPORT Human Clinical

"Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases."

Gives both the frequency and the specificity of the lesion against a 700-patient comparison cohort of steroid-resistant nephrotic syndrome.

PMID:9607189 SUPPORT Human Clinical

"Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases."

Documents the biopsy finding in a WT1-mutant early-onset nephrotic syndrome series.

Proteinuria HP:0000093

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"proteinuria every six months until age ten years, yearly thereafter"

Proteinuria is the surveillance parameter GeneReviews monitors for first appearance of the glomerulopathy.

Stage 5 Chronic Kidney Disease VERY_FREQUENT HP:0003774

Show evidence (1 reference)

PMID:9607189 SUPPORT Human Clinical

"End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients."

Quantifies the rapid progression to kidney failure.

Gonadal Dysgenesis FREQUENT HP:0000133

Show evidence (1 reference)

PMID:24402088 SUPPORT Human Clinical

"Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease."

Quantifies urogenital involvement and its specificity to WT1 disease.

Ambiguous Genitalia HP:0000062

Show evidence (1 reference)

PMID:9607189 SUPPORT Human Clinical

"From the seven genotypic males with WT1 mutations, five presented ambiguous genitalia and two a female phenotype."

Documents the external genital phenotype in genotypic males.

Nephroblastoma FREQUENT HP:0002667

Show evidence (2 references)

PMID:24402088 SUPPORT Human Clinical

"Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease."

Gives the Wilms tumor frequency in a WT1 nephropathy cohort.

PMID:9607189 SUPPORT Human Clinical

"A unilateral Wilms' tumor was found before or concomitant with NS in four children (3 males, 1 female)."

Documents Wilms tumor presenting at or before the renal phenotype.

Gonadoblastoma OCCASIONAL HP:0000150

Show evidence (1 reference)

PMID:24402088 SUPPORT Human Clinical

"Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease."

Gives the gonadoblastoma frequency in WT1 disease.

🧬

Genetic Associations

1

WT1 (Heterozygous constitutional missense variants in the WT1 zinc finger DNA binding domain, clustered in exons 8 and 9, are the cause of Denys-Drash syndrome.)

Gene: WT1 hgnc:12796 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:9607189 SUPPORT Human Clinical

"four children presented the so-called hot spot mutation in exon 9 (R394N) and six had different mutations in exons 8 and 9 (4 not previously described)"

Documents the exon 8 and 9 clustering and the recurrent zinc-finger III hot spot.

PMID:24402088 SUPPORT Human Clinical

"Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD."

Establishes the genotype-phenotype association between DNA-binding-residue missense variants and the Denys-Drash renal phenotype.

PMID:24402088 SUPPORT Human Clinical

"Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome."

Records the contrasting truncating-variant phenotype, which is why Wilms risk cannot be read off the Denys-Drash label alone.

💊

Medical Actions

7

RAAS Inhibition for Proteinuria

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Renin angiotensin aldosterone system blockade is used to reduce proteinuria. Immunosuppression is explicitly avoided, since the glomerulopathy is genetic rather than immune mediated.

Mechanism Target:

Steroid-Resistant Nephrotic Syndrome

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"SRNS: avoid immunosuppressants; consider renin-angiotensin-aldosterone system (RAAS) inhibition."

GeneReviews management recommendation for the glomerulopathy.

Avoidance of Immunosuppressive Therapy

Action: Supportive Care NCIT:C15747

An explicit agents to avoid recommendation. Immunosuppressants used empirically for steroid resistant nephrotic syndrome are ineffective here and carry toxicity, which is a practical reason to establish the WT1 genotype early.

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic."

The GeneReviews agents and circumstances to avoid statement.

Prophylactic Gonadectomy

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Removal of dysgenetic gonadal tissue in individuals with a disorder of testicular development, to prevent gonadoblastoma.

Mechanism Target:

Gonadoblastoma

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"Prevent whenever possible gonadoblastoma by prophylactic gonadectomy in those with a disorder of testicular development."

GeneReviews prevention recommendation.

Wilms Tumor Surveillance

Action: Cancer Screening NCIT:C15406

Renal imaging every three months until age seven years. This entry classifies the syndrome as a cancer predisposition, so the tumor arm of the surveillance protocol belongs here alongside the proteinuria monitoring already recorded.

Mechanism Target:

Nephroblastoma

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"Wilms tumor every three months until age seven years"

The GeneReviews tumor surveillance interval.

Wilms Tumor Treatment

Action: Therapeutic Procedure NCIT:C49236

Standard oncology protocols, with nephron-sparing surgery where applicable. The nephron-sparing qualifier matters more here than in sporadic Wilms tumor, because these patients are already losing renal function to the glomerulopathy.

Mechanism Target:

Nephroblastoma

Show evidence (1 reference)

PMID:32352694 SUPPORT Human Clinical

"Treat Wilms tumor with standard oncology protocols and, when applicable, nephron-sparing surgery."

The GeneReviews treatment recommendation for the tumor.

Dialysis

Action: Dialysis NCIT:C15221

Peritoneal or haemodialysis for the kidney failure that follows the glomerulopathy, typically within months of nephrotic syndrome onset. Timing of diaphragmatic hernia repair is explicitly sequenced around starting peritoneal dialysis.

Mechanism Target:

Stage 5 Chronic Kidney Disease

Show evidence (1 reference)

PMID:32352694 SUPPORT INDIRECT Human Clinical

"Diaphragmatic hernia repair prior to the start of peritoneal dialysis."

Supports dialysis being anticipated in management by an inference step: the recommendation sequences other surgery around starting it rather than recommending dialysis outright.

Kidney Transplantation

Action: Kidney Transplantation NCIT:C15265

Platform: Surgery

The definitive kidney replacement arm. Graft recurrence of the glomerulopathy is not expected, since the lesion is driven by the constitutional WT1 variant acting in the native kidney rather than by a circulating factor.

Mechanism Target:

Stage 5 Chronic Kidney Disease

Show evidence (1 reference)

PMID:9607189 SUPPORT INDIRECT Human Clinical

"End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients."

Establishes by inference that definitive kidney replacement is part of the expected course: the paper reports how fast kidney failure arrives, not the transplant itself.

🔬

Diagnosis

1

Molecular confirmation of WT1 disorder

The diagnosis is established by finding a heterozygous WT1 pathogenic variant in someone with suggestive clinical findings. Establishing the genotype early is not academic here: it is what stops ineffective and toxic immunosuppression being given for the steroid resistant nephrotic syndrome, and what triggers Wilms tumor surveillance and gonadal management.

Genetic Testing NCIT:C15709

Show evidence (2 references)

PMID:32352694 SUPPORT Human Clinical

"The diagnosis of WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing."

The GeneReviews statement of how the diagnosis is established.

PMID:24402088 SUPPORT Human Clinical

"We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening."

Supports testing the whole steroid-resistant nephrotic syndrome population rather than only those with the full triad, which is how these patients are actually found.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Denys-Drash Syndrome:

Frasier syndrome MONDO:0007635

Overlapping Features The other pole of the WT1 continuum. Frasier syndrome arises from intron 9 splice donor variants that reduce the +KTS isoform without producing a mutant protein, and presents with focal segmental glomerulosclerosis, later kidney failure, and complete gonadal dysgenesis rather than diffuse mesangial sclerosis with early kidney failure.

Distinguishing Features

Diffuse mesangial sclerosis with kidney failure usually before age five favors Denys-Drash syndrome.
Focal segmental glomerulosclerosis with later kidney failure and complete gonadal dysgenesis favors Frasier syndrome.
A zinc finger missense variant favors Denys-Drash syndrome; an intron 9 splice donor variant favors Frasier syndrome.

Show evidence (2 references)

PMID:9499425 SUPPORT Human Clinical

"Here we show that a related disease, Frasier syndrome, characterized by focal glomerular sclerosis, delayed kidney failure and complete gonadal dysgenesis, is probably caused by specific intronic point mutations of WT1 that preferentially affect a CpG dinucleotide."

Defines the Frasier phenotype and its distinct splice mechanism.

PMID:9499425 SUPPORT Human Clinical

"In contrast to Denys-Drash syndrome, no mutant protein is produced."

States the mechanistic contrast that separates the two entities, dominant-negative protein versus isoform imbalance.

🐁

Animal Models

1

Wt1 R394W knock-in mouse

A mouse line carrying the human zinc-finger III hot-spot substitution, generated to identify the podocyte transcriptional program that WT1 controls and whose loss produces the diffuse mesangial sclerosis lesion.

Species

Mouse

Genotype

Wt1 p.R394W heterozygous knock-in

Publication

PMID:19797313

Pathograph links

Loss of the WT1 Transcriptional Program in Podocytes recapitulates fidelity: high The model reproduces the diffuse mesangial sclerosis nephropathy and was used to identify direct podocyte WT1 target genes by expression profiling and ChIP.

Limitations: The model speaks to the renal arm only. The gonadal and tumor components of the human syndrome are not part of the reported phenotype, so it cannot be used to argue about those.

Readouts

Podocyte WT1 target gene expression

Direction: DECREASED

Interpretation: Sciellin and Sulf1 are expressed in wild-type podocytes and strongly down-regulated in mutants, identifying the program the variant disrupts.

Show evidence (1 reference)

PMID:19797313 SUPPORT Model Organism

"Scel, encoding sciellin, a protein of the cornified envelope in the skin, and Sulf1, encoding a 6-O endosulfatase, are shown to be expressed in wild-type podocytes and to be strongly down-regulated in mutants."

The expression measurement identifying the down-regulated targets.

Show evidence (1 reference)

PMID:19797313 SUPPORT Model Organism

"To identify podocyte WT1 targets, we generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli and identified excellent candidates that may modify podocyte differentiation and growth factor signaling in glomeruli."

Establishes the model as purpose-built for this node, and that it reproduces the diffuse mesangial sclerosis phenotype.

{ }

Source YAML

click to show

name: Denys-Drash Syndrome
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Pediatric Cancer
- Disorder of Sex Development
- Glomerular Disease
parents:
- hereditary cancer-predisposing syndrome
- 46,XY disorder of sex development
disease_term:
  preferred_term: Denys-Drash syndrome
  term:
    id: MONDO:0008682
    label: Denys-Drash syndrome
synonyms:
- Drash syndrome
- DDS
- nephropathy associated with male pseudohermaphroditism and Wilms tumor
description: >-
  Denys-Drash syndrome is a constitutional WT1 disorder classically defined by the
  triad of early onset diffuse mesangial sclerosis with steroid resistant nephrotic
  syndrome, gonadal dysgenesis in genotypic males, and a high risk of Wilms tumor.
  The causative variants are heterozygous missense changes clustered in the zinc
  finger DNA binding domain, most often in exon 9 (zinc finger III) and exon 8
  (zinc finger II). Because the altered protein retains its N terminal domain and
  can still act on the wild type WT1 present in the same cell, the mechanism is
  understood as dominant negative interference with WT1 target recognition rather
  than simple haploinsufficiency, which distinguishes it from the whole gene
  deletions of WAGR spectrum.
  A nosological caveat belongs at the top of this entry rather than buried in a
  note. Contemporary expert practice no longer treats Denys-Drash as a discrete
  clinical diagnosis: the GeneReviews WT1 Disorder chapter states that Denys-Drash
  and Frasier syndrome are part of one phenotypic continuum and are no longer
  clinically helpful designations. This entry is curated because MONDO carries the
  term and the historical literature is indexed under it, and because the zinc
  finger missense mechanism it names is genuinely distinct from the intron 9 splice
  mechanism of Frasier syndrome. It should be read as one pole of the WT1
  continuum, not as a separate disease. The grouping
  kb/groupings/WT1_Disorders.yaml records that continuum explicitly.
inheritance:
- name: Autosomal dominant, usually de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous WT1 zinc finger variants act dominantly. Most probands carry a de
    novo variant, though transmission from an affected or mosaic parent is
    documented.
  evidence:
  - reference: PMID:1655284
    reference_title: "Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two families analyzed, the mutations were shown to arise de novo."
    explanation: Establishes the de novo origin typical of the syndrome.
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WT1 disorder is inherited in an autosomal dominant manner."
    explanation: GeneReviews states the mode of inheritance for the WT1 disorder spectrum.
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in rare instances, a parent of an individual with WT1 disorder is heterozygous for the pathogenic variant identified in the proband"
    explanation: Documents transmission from an affected parent, the first half of the inheritance claim.
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the WT1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism."
    explanation: >-
      Documents parental gonadal mosaicism and its effect on sibling recurrence risk,
      the second half of the claim.
pathophysiology:
- name: WT1 Zinc-Finger Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous constitutional point mutation in the WT1 zinc finger region,
    clustered in the exons encoding zinc fingers 2 and 3, alters the residues that
    make base specific contacts with target DNA.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Heterozygous missense substitutions in the WT1 zinc finger DNA binding domain,
      clustered in exons 8 and 9, with a recurrent hot spot at zinc finger III. The
      phenotype requires an intact N terminal region alongside disrupted zinc finger
      function, which is the argument for dominant negative rather than
      haploinsufficient action.
  molecular_functions:
  - preferred_term: WT1 sequence-specific DNA binding
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Biallelic WT1 Inactivation in Nephrogenic Rests
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The constitutional variant is the first hit; tumor initiation additionally
      requires a somatic event at the remaining allele.
  - target: Dominant-Negative Interference with WT1 Target Recognition
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:1655284
      reference_title: "Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition."
      explanation: >-
        States that the zinc finger variants act by disrupting DNA sequence
        recognition, which is the step this edge asserts.
  evidence:
  - reference: PMID:1655284
    reference_title: "Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found."
    explanation: Establishes the heterozygous zinc-finger variant as the constitutional lesion.
  - reference: PMID:8388765
    reference_title: "Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The WT1 mutations in these patients are constitutional point mutations clustered in the zinc finger (ZF) encoding exons, particularly the exons encoding ZF2 and ZF3."
    explanation: Localizes the variants to the zinc-finger 2 and 3 exons.
- name: Dominant-Negative Interference with WT1 Target Recognition
  biological_scale: MOLECULAR
  description: >-
    The mutant protein retains its intact N terminal domain and interferes with the
    wild type WT1 present in the same cell, either by blocking its access to normal
    binding sites or by directing the complex to inappropriate ones. This is why the
    phenotype is more severe than that of a WT1 whole gene deletion.
  downstream:
  - target: Loss of the WT1 Transcriptional Program in Podocytes
    causal_link_type: DIRECT
  - target: Failure of Gonadal Somatic Cell Differentiation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:8388765
    reference_title: "Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we suggest that a dominant negative mechanism is at work here"
    explanation: >-
      The primary report proposing dominant-negative action, on the argument that the
      phenotype requires an intact N-terminus alongside disrupted zinc-finger function.
  - reference: PMID:9499425
    reference_title: "Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A much more severe phenotype is seen in patients with Denys-Drash syndrome which results from heterozygous dominant-negative mutations of the gene."
    explanation: >-
      Contrasts the dominant-negative mechanism here with the loss of the +KTS isoform
      in Frasier syndrome, where no mutant protein is made.
- name: Loss of the WT1 Transcriptional Program in Podocytes
  biological_scale: CELLULAR
  description: >-
    WT1 is required in the mature glomerulus, where it is highly expressed in
    podocytes and directs a transcriptional program governing podocyte
    differentiation and podocyte to mesangial cross talk. Its disruption is the
    proximate cellular lesion behind the glomerulopathy.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: glomerulus development
    term:
      id: GO:0032835
      label: glomerulus development
    modifier: DECREASED
  downstream:
  - target: Diffuse Mesangial Sclerosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19797313
      reference_title: "A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Their defects are thought to modify the cross-talk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS) a nephropathy associated with WT1 mutations."
      explanation: >-
        States the causal step from disrupted podocyte WT1 targets to the mesangial
        sclerosis lesion.
  evidence:
  - reference: PMID:19797313
    reference_title: "A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By ChIP we show that Scel and Sulf1 are direct WT1 targets."
    explanation: >-
      A diffuse mesangial sclerosis mouse line identifies direct podocyte WT1 target
      genes, substantiating a podocyte transcriptional program under WT1 control.
- name: Failure of Gonadal Somatic Cell Differentiation
  biological_scale: TISSUE
  description: >-
    The same WT1 program is required for testicular somatic cell differentiation, so
    genotypic males show partial to complete gonadal dysgenesis with under
    virilization, and dysgenetic gonadal tissue carries gonadoblastoma risk.
  biological_processes:
  - preferred_term: sex differentiation
    term:
      id: GO:0007548
      label: sex differentiation
    modifier: DECREASED
  downstream:
  - target: Gonadal Dysgenesis
    causal_link_type: DIRECT
  - target: Ambiguous Genitalia
    causal_link_type: DIRECT
  - target: Gonadoblastoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysgenetic gonadal tissue is the substrate for gonadoblastoma, which is why
      prophylactic gonadectomy is offered.
  evidence:
  - reference: PMID:1655284
    reference_title: "Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development."
    explanation: Links the WT1 lesion to urogenital developmental failure.
- name: Diffuse Mesangial Sclerosis
  biological_scale: TISSUE
  description: >-
    The characteristic renal biopsy lesion, an expansion of mesangial matrix with
    podocyte hypertrophy progressing to global glomerular sclerosis. It is largely
    specific to WT1 disease among steroid resistant nephrotic syndrome cohorts and is
    the lesion that drives rapid progression to kidney failure.
  cell_types:
  - preferred_term: glomerular mesangial cell
    term:
      id: CL:1000742
      label: glomerular mesangial cell
  downstream:
  - target: Steroid-Resistant Nephrotic Syndrome
    causal_link_type: DIRECT
  - target: Proteinuria
    causal_link_type: DIRECT
  - target: Stage 5 Chronic Kidney Disease
    causal_link_type: DIRECT
  - target: Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases."
    explanation: >-
      Establishes diffuse mesangial sclerosis as the WT1-specific lesion against a
      700-patient steroid-resistant nephrotic syndrome comparison cohort.
  - reference: PMID:9607189
    reference_title: "Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases."
    explanation: Documents the biopsy lesion in a WT1-mutant early-onset nephrotic syndrome series.
- name: Biallelic WT1 Inactivation in Nephrogenic Rests
  biological_scale: CELLULAR
  description: >-
    A somatic second hit at the remaining WT1 allele within persisting nephrogenic
    rests completes tumor suppressor inactivation and initiates Wilms tumor, the
    classical two hit sequence acting on a constitutional first hit.
  genetic_context:
    variant_origin: SOMATIC
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Reduction to homozygosity for the mutant WT1 allele within tumor tissue,
      observed as loss of the wild type allele.
  downstream:
  - target: Nephroblastoma
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:1655284
    reference_title: "Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele."
    explanation: >-
      Demonstrates loss of the wild-type allele in the tumors themselves, which is the
      somatic second hit this node asserts.
phenotypes:
- category: Renal
  name: Steroid-Resistant Nephrotic Syndrome
  description: >-
    Congenital, infantile, or early childhood onset nephrotic syndrome that does not
    respond to corticosteroids and progresses rapidly.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy."
    explanation: GeneReviews names steroid-resistant nephrotic syndrome as the defining renal phenotype.
- category: Renal
  name: Diffuse Mesangial Sclerosis
  description: >-
    The defining renal biopsy lesion. It is recorded as a phenotype in addition to the
    pathophysiology node of the same name because it is what a nephropathologist
    reports, and because it is the finding that distinguishes WT1 disease from other
    causes of steroid resistant nephrotic syndrome.
  phenotype_term:
    preferred_term: Diffuse mesangial sclerosis
    term:
      id: HP:0001967
      label: Diffuse mesangial sclerosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases."
    explanation: >-
      Gives both the frequency and the specificity of the lesion against a 700-patient
      comparison cohort of steroid-resistant nephrotic syndrome.
  - reference: PMID:9607189
    reference_title: "Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases."
    explanation: Documents the biopsy finding in a WT1-mutant early-onset nephrotic syndrome series.
- category: Renal
  name: Proteinuria
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "proteinuria every six months until age ten years, yearly thereafter"
    explanation: >-
      Proteinuria is the surveillance parameter GeneReviews monitors for first
      appearance of the glomerulopathy.
- category: Renal
  name: Stage 5 Chronic Kidney Disease
  description: >-
    Kidney failure, typically reached within months of nephrotic syndrome onset and
    commonly before age five years.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:9607189
    reference_title: "Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients."
    explanation: Quantifies the rapid progression to kidney failure.
- category: Cardiovascular
  name: Hypertension
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression."
    explanation: Reports hypertension at presentation as more frequent in WT1 disease.
- category: Genitourinary
  name: Gonadal Dysgenesis
  description: >-
    Partial to complete failure of testicular development in genotypic males,
    presenting as ambiguous genitalia or a female external phenotype.
  phenotype_term:
    preferred_term: Gonadal dysgenesis
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
  frequency: FREQUENT
  evidence:
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease."
    explanation: Quantifies urogenital involvement and its specificity to WT1 disease.
- category: Genitourinary
  name: Ambiguous Genitalia
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  evidence:
  - reference: PMID:9607189
    reference_title: "Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From the seven genotypic males with WT1 mutations, five presented ambiguous genitalia and two a female phenotype."
    explanation: Documents the external genital phenotype in genotypic males.
- category: Neoplastic
  name: Nephroblastoma
  description: >-
    Wilms tumor, often of early childhood onset and sometimes bilateral or
    multifocal, arising on the constitutional WT1 variant.
  phenotype_term:
    preferred_term: Nephroblastoma
    term:
      id: HP:0002667
      label: Nephroblastoma
  frequency: FREQUENT
  evidence:
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease."
    explanation: Gives the Wilms tumor frequency in a WT1 nephropathy cohort.
  - reference: PMID:9607189
    reference_title: "Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A unilateral Wilms' tumor was found before or concomitant with NS in four children (3 males, 1 female)."
    explanation: Documents Wilms tumor presenting at or before the renal phenotype.
- category: Neoplastic
  name: Gonadoblastoma
  description: >-
    Germ cell tumor arising in dysgenetic gonadal tissue, the reason prophylactic
    gonadectomy is offered.
  phenotype_term:
    preferred_term: Gonadoblastoma
    term:
      id: HP:0000150
      label: Gonadoblastoma
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease."
    explanation: Gives the gonadoblastoma frequency in WT1 disease.
genetic:
- name: WT1
  gene_term:
    preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Heterozygous constitutional missense variants in the WT1 zinc finger DNA binding
    domain, clustered in exons 8 and 9, are the cause of Denys-Drash syndrome.
  notes: >-
    The recurrent hot spot lies in zinc finger III, encoded by exon 9. Genotype
    tracks with phenotype across the WT1 spectrum: missense substitutions at DNA
    binding residues give the diffuse mesangial sclerosis picture of Denys-Drash,
    truncating variants carry the highest Wilms tumor risk, and intronic KTS variants
    give the Frasier picture.
  evidence:
  - reference: PMID:9607189
    reference_title: "Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four children presented the so-called hot spot mutation in exon 9 (R394N) and six had different mutations in exons 8 and 9 (4 not previously described)"
    explanation: Documents the exon 8 and 9 clustering and the recurrent zinc-finger III hot spot.
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD."
    explanation: >-
      Establishes the genotype-phenotype association between DNA-binding-residue
      missense variants and the Denys-Drash renal phenotype.
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome."
    explanation: >-
      Records the contrasting truncating-variant phenotype, which is why Wilms risk
      cannot be read off the Denys-Drash label alone.
treatments:
- name: RAAS Inhibition for Proteinuria
  description: >-
    Renin angiotensin aldosterone system blockade is used to reduce proteinuria.
    Immunosuppression is explicitly avoided, since the glomerulopathy is genetic
    rather than immune mediated.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Steroid-Resistant Nephrotic Syndrome
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SRNS: avoid immunosuppressants; consider renin-angiotensin-aldosterone system (RAAS) inhibition."
    explanation: GeneReviews management recommendation for the glomerulopathy.
- name: Avoidance of Immunosuppressive Therapy
  description: >-
    An explicit agents to avoid recommendation. Immunosuppressants used empirically
    for steroid resistant nephrotic syndrome are ineffective here and carry toxicity,
    which is a practical reason to establish the WT1 genotype early.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic."
    explanation: The GeneReviews agents and circumstances to avoid statement.
- name: Prophylactic Gonadectomy
  description: >-
    Removal of dysgenetic gonadal tissue in individuals with a disorder of testicular
    development, to prevent gonadoblastoma.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Gonadoblastoma
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevent whenever possible gonadoblastoma by prophylactic gonadectomy in those with a disorder of testicular development."
    explanation: GeneReviews prevention recommendation.
- name: Wilms Tumor Surveillance
  description: >-
    Renal imaging every three months until age seven years. This entry classifies the
    syndrome as a cancer predisposition, so the tumor arm of the surveillance protocol
    belongs here alongside the proteinuria monitoring already recorded.
  treatment_term:
    preferred_term: Cancer Screening
    term:
      id: NCIT:C15406
      label: Cancer Screening
  target_mechanisms:
  - target: Nephroblastoma
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wilms tumor every three months until age seven years"
    explanation: The GeneReviews tumor surveillance interval.
- name: Wilms Tumor Treatment
  description: >-
    Standard oncology protocols, with nephron-sparing surgery where applicable. The
    nephron-sparing qualifier matters more here than in sporadic Wilms tumor, because
    these patients are already losing renal function to the glomerulopathy.
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Nephroblastoma
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treat Wilms tumor with standard oncology protocols and, when applicable, nephron-sparing surgery."
    explanation: The GeneReviews treatment recommendation for the tumor.
- name: Dialysis
  description: >-
    Peritoneal or haemodialysis for the kidney failure that follows the glomerulopathy,
    typically within months of nephrotic syndrome onset. Timing of diaphragmatic hernia
    repair is explicitly sequenced around starting peritoneal dialysis.
  treatment_term:
    preferred_term: Dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  target_mechanisms:
  - target: Stage 5 Chronic Kidney Disease
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Diaphragmatic hernia repair prior to the start of peritoneal dialysis."
    explanation: >-
      Supports dialysis being anticipated in management by an inference step: the
      recommendation sequences other surgery around starting it rather than recommending
      dialysis outright.
- name: Kidney Transplantation
  description: >-
    The definitive kidney replacement arm. Graft recurrence of the glomerulopathy is not
    expected, since the lesion is driven by the constitutional WT1 variant acting in the
    native kidney rather than by a circulating factor.
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Stage 5 Chronic Kidney Disease
  evidence:
  - reference: PMID:9607189
    reference_title: "Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients."
    explanation: >-
      Establishes by inference that definitive kidney replacement is part of the expected
      course: the paper reports how fast kidney failure arrives, not the transplant itself.
diagnosis:
- name: Molecular confirmation of WT1 disorder
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    The diagnosis is established by finding a heterozygous WT1 pathogenic variant in
    someone with suggestive clinical findings. Establishing the genotype early is not
    academic here: it is what stops ineffective and toxic immunosuppression being given
    for the steroid resistant nephrotic syndrome, and what triggers Wilms tumor
    surveillance and gonadal management.
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing."
    explanation: The GeneReviews statement of how the diagnosis is established.
  - reference: PMID:24402088
    reference_title: "Genotype-phenotype associations in WT1 glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening."
    explanation: >-
      Supports testing the whole steroid-resistant nephrotic syndrome population rather
      than only those with the full triad, which is how these patients are actually found.
animal_models:
- name: Wt1 R394W knock-in mouse
  species: Mouse
  genotype: Wt1 p.R394W heterozygous knock-in
  publication: PMID:19797313
  description: >-
    A mouse line carrying the human zinc-finger III hot-spot substitution, generated to
    identify the podocyte transcriptional program that WT1 controls and whose loss
    produces the diffuse mesangial sclerosis lesion.
  modeled_mechanisms:
  - target: Loss of the WT1 Transcriptional Program in Podocytes
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The model reproduces the diffuse mesangial sclerosis nephropathy and was used to
      identify direct podocyte WT1 target genes by expression profiling and ChIP.
    limitations: >-
      The model speaks to the renal arm only. The gonadal and tumor components of the
      human syndrome are not part of the reported phenotype, so it cannot be used to
      argue about those.
    readouts:
    - name: Podocyte WT1 target gene expression
      target: Loss of the WT1 Transcriptional Program in Podocytes
      direction: DECREASED
      interpretation: >-
        Sciellin and Sulf1 are expressed in wild-type podocytes and strongly
        down-regulated in mutants, identifying the program the variant disrupts.
      evidence:
      - reference: PMID:19797313
        reference_title: "A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Scel, encoding sciellin, a protein of the cornified envelope in the skin, and Sulf1, encoding a 6-O endosulfatase, are shown to be expressed in wild-type podocytes and to be strongly down-regulated in mutants."
        explanation: The expression measurement identifying the down-regulated targets.
    evidence:
    - reference: PMID:19797313
      reference_title: "A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To identify podocyte WT1 targets, we generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli and identified excellent candidates that may modify podocyte differentiation and growth factor signaling in glomeruli."
      explanation: >-
        Establishes the model as purpose-built for this node, and that it reproduces the
        diffuse mesangial sclerosis phenotype.
differential_diagnoses:
- name: Frasier syndrome
  disease_term:
    preferred_term: Frasier syndrome
    term:
      id: MONDO:0007635
      label: Frasier syndrome
  description: >-
    The other pole of the WT1 continuum. Frasier syndrome arises from intron 9 splice
    donor variants that reduce the +KTS isoform without producing a mutant protein,
    and presents with focal segmental glomerulosclerosis, later kidney failure, and
    complete gonadal dysgenesis rather than diffuse mesangial sclerosis with early
    kidney failure.
  distinguishing_features:
  - Diffuse mesangial sclerosis with kidney failure usually before age five favors Denys-Drash syndrome.
  - Focal segmental glomerulosclerosis with later kidney failure and complete gonadal dysgenesis favors Frasier syndrome.
  - A zinc finger missense variant favors Denys-Drash syndrome; an intron 9 splice donor variant favors Frasier syndrome.
  evidence:
  - reference: PMID:9499425
    reference_title: "Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that a related disease, Frasier syndrome, characterized by focal glomerular sclerosis, delayed kidney failure and complete gonadal dysgenesis, is probably caused by specific intronic point mutations of WT1 that preferentially affect a CpG dinucleotide."
    explanation: Defines the Frasier phenotype and its distinct splice mechanism.
  - reference: PMID:9499425
    reference_title: "Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to Denys-Drash syndrome, no mutant protein is produced."
    explanation: >-
      States the mechanistic contrast that separates the two entities, dominant-negative
      protein versus isoform imbalance.
discussions:
- discussion_id: wt1_continuum_vs_discrete_entity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Should Denys-Drash syndrome remain a distinct knowledge base entry, given that
    expert clinical practice has folded it into a WT1 disorder continuum?
  attaches_to:
  - disease#Denys-Drash Syndrome
  rationale: >-
    The GeneReviews WT1 Disorder chapter states that the Denys-Drash and Frasier
    designations are no longer clinically helpful and describes one phenotypic
    continuum. MONDO still carries separate terms, and there is no MONDO umbrella term
    for the continuum to bind, so the knowledge base cannot simply follow the clinical
    reframing. The mechanistic distinction is also real, a zinc finger missense
    dominant negative versus an intron 9 splice isoform imbalance, so collapsing the
    entries would lose a genuine mechanistic contrast. This entry is retained on that
    basis, with kb/groupings/WT1_Disorders.yaml carrying the continuum, and the
    question is recorded rather than silently resolved.
  evidence:
  - reference: PMID:32352694
    reference_title: "WT1 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful"
    explanation: >-
      The GeneReviews statement that motivates this gap, quoted so the entry does not
      assert a nosology its own baseline source contradicts.
references:
- reference: PMID:32352694
  title: WT1 Disorder
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:32352694

WT1 Disorder

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Address review on PR #10448 (Denys-Drash) · 2026-09-01T23:26:26Z · View source

Response to the ai4c-reviewer CHANGES_REQUESTED review on PR #10448. Six items, all fixed. Item 2 was a genuine error, and one the PR description made worse. The review found that diffuse mesangial sclerosis, the disease-defining lesion, had no HPO binding and no phenotype entry, and that the PR body's claim that 'HP:0001967 is used instead' was not true of the diff. Verified: HP:0001967 appeared nowhere in the file. What happened is that the wrong CURIE from the deep-research report (HP:0005567, Renal magnesium wasting) was correctly rejected, the right term was looked up, and then the lesion was modeled only as a pathophysiology node with a CL cell-type binding, so the HP term never entered the entry. Diffuse Mesangial Sclerosis now exists as a bound phenotype alongside the pathophysiology node of the same name, and the PR description has been corrected. Item 1, reference_title: added to all evidence items, verbatim from each references_cache frontmatter. Item 3, GeneReviews DIAGNOSIS/TESTING unmined: added a diagnosis: block. The reviewer's observation that the entry argued for immunosuppression avoidance on the grounds of establishing the WT1 genotype early, then never modeled establishing it, was correct; the block description now makes that link explicit. Item 4, Wilms tumor surveillance: restored. This was dropped during initial curation for a traceable reason recorded in the first history record: NCIT:C17167 turned out to be Statistics rather than Screening, and the treatment was removed rather than rebound. NCIT:C15406 (Cancer Screening) is the correct term and is now used. Item 5, kidney replacement therapy and Wilms tumor treatment: both added. The entry established ESRD within four months in 7/10 patients and offered no treatment addressing it, which was a real gap. Item 6, Ratelade 2010 Wt1 R394W knock-in mouse: added as an animal_models entry, RECAPITULATES against the podocyte transcriptional program node, with a target-gene expression readout. Limitations record that the model speaks to the renal arm only. Non-blocking suggestions not taken this round, with reasons. The clinical_trials gap (NCT01252901) and a progression: section are both real but need their own sourcing pass rather than being assembled from what is already cached. The uncited 'transmission from an affected or mosaic parent' claim was noted by the reviewer as unfixable from PMID:1327525, whose cache is title-only; it is left as prose for now. Validation: validate-disorders passes; 41/41 snippets verified; 41/41 evidence items carry reference_title; entity-ref, causal-target, duplicate-key, enum-value, title-snippet, snippet-length and snippet-grading gates clean; the WT1_Disorders grouping still validates with all three members SATISFIED.

Create: Denys-Drash Syndrome · 2026-09-01T19:05:24Z · View source

De novo curation of Denys-Drash syndrome (MONDO:0008682, WT1) from a falcon/Edison deep-research report (research/Denys-Drash_Syndrome-deep-research-falcon.md) plus independent PubMed searching, with the GeneReviews WT1 Disorder chapter (PMID:32352694) as the mandatory phenotype baseline. The falcon report was citation-thin: its sidecar contained only the query, and the body yielded 3 resolvable references and 4 DOIs, of which one (Ratelade 2010, PMID:19797313) was a usable primary source. Most references were therefore found independently, seeded by the PMID list the report surfaced from an Open Targets query. Evidence rests on PMID:1655284 (Pelletier, germline zinc-finger variants and tumor LOH), PMID:8388765 (dominant-negative mechanism), PMID:9607189 and PMID:24402088 (genotype-phenotype and cohort frequencies), PMID:19797313 (podocyte WT1 targets in a DMS mouse line), and PMID:9499425 (Frasier contrast). Two corrections against the report were applied rather than inherited. Its term-validation section flagged HP:0005567 (Renal magnesium wasting) as bound to a row describing diffuse mesangial sclerosis; the correct term HP:0001967 was used instead, and the wrong CURIE was not carried into the entry. Its UBERON:0000473 (testis) binding for a generic 'gonads' row was likewise not reused. Nosology: the GeneReviews chapter states that Denys-Drash and Frasier are one phenotypic continuum and are no longer clinically helpful designations. MONDO has no umbrella term for that continuum, so the entry is retained on MONDO:0008682 with the continuum recorded in the description, Frasier in differential_diagnoses, an OPEN KNOWLEDGE_GAP discussion, and a new kb/groupings/WT1_Disorders.yaml uniting Denys-Drash, WAGR, and Meacham. This framing was chosen by the curator, not assumed. Named Entity Confusion preflight PASS (WT1 mentioned 88 times; MONDO OMIM 194080). Validation: just validate passed; 31/31 snippets verified; validate-terms passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading all clean. Stub stubs/Denys-Drash_Syndrome.yaml deleted.

Falcon ▸

Denys–Drash Syndrome: Disease-Characteristics Research Report

Edison Scientific Literature 6 citations 2026-09-01T17:00:11.678445

Denys–Drash Syndrome: Disease-Characteristics Research Report

Executive summary

Denys–Drash syndrome (DDS) is a very rare, usually de novo autosomal-dominant WT1-related disorder. Its canonical clinical triad is (1) congenital or early-childhood steroid-resistant nephrotic syndrome, usually caused by diffuse mesangial sclerosis (DMS); (2) predisposition to Wilms tumor; and (3) a disorder/difference of sex development (DSD), particularly gonadal dysgenesis and undervirilization in individuals with a 46,XY karyotype. Modern practice increasingly treats DDS as the severe, early-onset end of a continuous spectrum of WT1-associated nephropathy rather than as a completely discrete molecular entity. Open Targets identifies WT1 as the overwhelmingly strongest disease-associated target and maps DDS to MONDO:0008682. (OpenTargets Search: Denys-Drash syndrome-WT1, ratelade2010amurinemodel pages 1-2, ahmad2019theroleof pages 25-29)

The strongest mechanistic evidence comes from engineered mice and podocyte systems. A heterozygous WT1 zinc-finger mutation disrupts the transcriptional programs that establish and maintain podocyte identity, filtration-barrier architecture, and glomerular signaling. This produces proteinuria, DMS, and rapidly progressive kidney failure. Separately, impaired WT1-dependent genitourinary development contributes to 46,XY DSD, while loss of tumor-suppressor function in susceptible renal precursor cells predisposes to nephroblastoma. (ratelade2010amurinemodel pages 1-2)

domain	evidence-based findings	ontology suggestions	evidence limitations
1. Disease information	Denys-Drash syndrome (DDS) is a rare Mendelian WT1-associated syndrome defined by the classic triad of early-onset nephropathy, Wilms tumor predisposition, and 46,XY disorder/difference of sex development (DSD); Open Targets lists disease identifier MONDO:0008682 and strongest target association with WT1. Evidence base is aggregated disease-level plus individual case/cohort reports, not EHR-derived population surveillance (OpenTargets Search: Denys-Drash syndrome-WT1, ahmad2019theroleof pages 25-29)	MONDO:0008682; MeSH term suggestion: Denys-Drash Syndrome if used locally; NCIT disease term suggestion: Denys-Drash Syndrome	OMIM, Orphanet, ICD-10/11, and MeSH numeric identifiers were not verified in available tool context and should be left unfilled until source-confirmed
2. Etiology	Primary cause is heterozygous germline WT1 pathogenic variation, classically in exons 8 or 9 affecting zinc-finger DNA-binding domains; inheritance is autosomal dominant, but many cases are de novo. No established environmental or infectious causes were identified in available evidence (ahmad2019theroleof pages 25-29, NCT07605884 chunk 1)	HGNC: WT1; SO variant classes: missense_variant, frameshift_variant, splice_donor_variant, splice_region_variant	Gene-environment interaction and protective factors are not established for DDS in available evidence
3. Phenotypes	Core renal phenotype is diffuse mesangial sclerosis (DMS) causing congenital/infantile nephrotic syndrome, proteinuria, edema, and progression to kidney failure, often before age 5; extrarenal phenotypes include Wilms tumor and male pseudohermaphroditism/46,XY DSD with ambiguous or female external genitalia (ratelade2010amurinemodel pages 1-2, ahmad2019theroleof pages 25-29)	HPO: HP:0000093 Proteinuria; HP:0000100 Nephrotic syndrome; HP:0005567 Diffuse mesangial sclerosis; HP:0003774 Stage 5 chronic kidney disease; HP:0000830 Ambiguous genitalia; HP:0000119 Abnormality of the genitourinary system; HP:0002667 Nephroblastoma	Precise phenotype frequencies vary by case series; robust pooled percentages were not available in retrieved context
4. Genetic/molecular information	WT1 is the main causal gene. Open Targets also shows weaker disease associations for GPC3 and WTIP, but these are not established primary causes of classic DDS. Functional consequence is loss of normal WT1 transcriptional regulation, with evidence supporting dominant-negative or threshold-reduction effects in some models (OpenTargets Search: Denys-Drash syndrome-WT1, ratelade2010amurinemodel pages 1-2)	HGNC:12796 WT1; GO:0003700 DNA-binding transcription factor activity; GO:0006355 regulation of DNA-templated transcription	Population allele frequencies, ClinVar classifications, and full variant catalog were not available from current tool context
5. Environmental information	No specific environmental, lifestyle, toxin, or infectious trigger is established as causal for DDS; disease is chiefly genetic (ahmad2019theroleof pages 25-29, NCT07605884 chunk 1)	ExO/CHEBI not clearly applicable	Absence of evidence should not be interpreted as proof of no modifiers; targeted environmental studies are lacking
6. Mechanism / pathophysiology	Causal chain: WT1 pathogenic variant leads to abnormal WT1 transcription factor function, which leads to impaired metanephric/podocyte developmental programs and altered podocyte identity, which leads to slit diaphragm/cytoskeletal and growth-factor dysregulation, which leads to DMS/proteinuria and progressive kidney failure; in parallel, abnormal genitourinary development leads to 46,XY DSD, and tumor-predisposition pathways increase Wilms tumor risk. Mouse and review evidence implicate WT1 control of FGF, BMP-pSMAD, FGF8/WNT4, and podocyte transcription factors MAFB, LMX1B, FOXC2, TCF21 (ratelade2010amurinemodel pages 1-2)	GO:0032835 glomerulus development; GO:0072006 nephron development; GO:1903671 regulation of sprouting angiogenesis; GO:0045666 positive regulation of neuron differentiation not primary; CL:0000653 podocyte; CL:0000099 mesangial cell; UBERON:0001285 glomerulus	Much detailed mechanism is inferred from mouse/review data rather than directly demonstrated in large human mechanistic cohorts
7. Anatomical structures affected	Primary organs: kidney and gonads/genitourinary tract; secondary oncologic involvement: kidney Wilms tumor. At tissue/cell level, glomerulus—especially podocytes and mesangium—is central. Subcellularly, WT1 is a nuclear transcription factor (ratelade2010amurinemodel pages 1-2, ahmad2019theroleof pages 25-29)	UBERON:0002113 kidney; UBERON:0001285 glomerulus; UBERON:0000473 gonad; CL:0000653 podocyte; CL:0000099 mesangial cell; GO:0005634 nucleus	Broader systemic involvement is limited in available evidence; lateralization is mainly relevant for unilateral/bilateral Wilms tumor but DDS-specific rates were not retrieved
8. Temporal development	Onset is typically congenital to early childhood for nephropathy; progression is rapid, with end-stage kidney disease (ESKD) often in early childhood. The transplant-focused study notes median transplant age 3.6 years in one French cohort description; registry/cohort evidence also supports early pediatric progression (ratelade2010amurinemodel pages 1-2, NCT07605884 chunk 1)	HPO onset modifiers: congenital onset, infantile onset, childhood onset	Natural-history staging data are sparse; remission is generally not expected without renal replacement/transplant strategies
9. Inheritance and population	DDS is rare, classically autosomal dominant, frequently sporadic/de novo. Sex-development manifestations are especially relevant in 46,XY individuals. No reliable prevalence/incidence estimate was available in current evidence. Registry evidence indicates need for multicenter collection due to rarity (ahmad2019theroleof pages 25-29, NCT07605884 chunk 1)	GENO:0000135 autosomal dominant inheritance; HPO: HP:0001417 X-linked not applicable	Penetrance, founder effects, carrier frequency, and population-specific prevalence could not be quantified from available context
10. Diagnostics	Diagnostic workup combines clinical suspicion (early nephrotic syndrome/DMS, Wilms tumor, ambiguous genitalia/46,XY DSD), kidney pathology, imaging for renal masses, karyotype/DSD assessment, and confirmatory WT1 molecular testing. Differential includes broader WT1-related disorders such as Frasier syndrome and isolated WT1 nephropathy (ahmad2019theroleof pages 25-29, NCT07605884 chunk 1)	HPO/NCIT suggestions: kidney biopsy, renal ultrasound, karyotyping, sequence analysis of WT1	No DDS-specific formal diagnostic criteria document was retrieved; recommendations are based on expert practice and WT1-related disorder literature
11. Outcome / prognosis	Morbidity is driven by steroid-resistant nephrotic syndrome, ESKD, tumor risk, DSD-related surgical/endocrine issues, and transplant complications. Recent registry/trial context highlights post-transplant lymphoproliferative disorder (PTLD) concern, with French data cited in protocol suggesting 20% PTLD risk versus ~4% in general transplant populations (NCT07605884 chunk 1)	HPO: HP:0003774 Stage 5 CKD; NCIT: renal replacement therapy; PTLD term suggestion	Survival and long-term life expectancy estimates were not available in current verified context
12. Treatment	No disease-modifying WT1-targeted therapy is established. Management is supportive and complication-directed: nephrotic syndrome care, nephrectomy in selected cases, dialysis, kidney transplantation, Wilms tumor treatment per pediatric oncology protocols, and multidisciplinary DSD care. Recent single-center WT1-associated transplant cohort reported no disease recurrence and preserved graft function after median 32 months, though not DDS-only (summarized in retrieved literature) (NCT07605884 chunk 1)	NCIT: Nephrectomy; Dialysis; Kidney Transplantation; Chemotherapy Regimen; Gonadectomy when indicated in DSD/WT1 care	Evidence is largely observational, retrospective, or extrapolated from WT1-associated disease and Wilms tumor management rather than DDS-specific trials
13. Prevention	Primary prevention of genetic occurrence is not available. Secondary prevention centers on early genetic diagnosis and tumor/renal surveillance in at-risk children; tertiary prevention involves CKD management, transplant planning, and long-term DSD/oncology follow-up. Genetic counseling is central for family planning (ahmad2019theroleof pages 25-29, NCT07605884 chunk 1)	NCIT: Genetic Counseling; Surveillance; Ultrasonography	Exact surveillance intervals were not source-verified in current context and should not be over-specified here
14. Other species / natural disease	No naturally occurring veterinary analogue was established in available context. Comparative relevance comes mainly from engineered mouse models rather than spontaneous disease in other species (ratelade2010amurinemodel pages 1-2)	NCBI Taxon suggestion if needed for negative annotation: Mus musculus 10090 for model, not natural disease	OMIA-style natural disease evidence was not retrieved
15. Model organisms and current research	Mouse DDS models carrying WT1 missense alleles (for example p.Arg394Trp) recapitulate glomerulosclerosis/DMS-like renal disease and identified altered podocyte transcriptional targets including Scel, Sulf1, and Cyp26a1; in vitro podocyte proteomic work supports dedifferentiation-associated changes. Current research is largely observational/registry-based, including WT1 mutation registry NCT01252901, UK rare kidney disease registry NCT06065852, rare disease natural history registry NCT01793168, and PTLD risk study NCT07605884 (ratelade2010amurinemodel pages 1-2, NCT07605884 chunk 1)	NCBI Taxon:10090; CL:0000653 podocyte; GO:0006351 transcription, DNA-templated; NCIT: Disease Registry	2023-2024 DDS-specific interventional trials, spatial transcriptomics, or multi-omics integration studies were not identified in available tool context

Table: This table summarizes evidence-based, knowledge-base-ready findings for Denys-Drash syndrome across all 15 requested domains. It highlights what is supported by available human, mouse, in vitro, and registry evidence while explicitly marking unverified identifiers and data gaps.

1. Disease information

Definition. DDS is a Mendelian developmental kidney and cancer-predisposition syndrome associated with heterozygous germline pathogenic variants in WT1, encoding the WT1 transcription factor. The historical triad comprises progressive nephropathy/DMS, Wilms tumor, and 46,XY DSD (“male pseudohermaphroditism” in older literature). Not every affected person has all three manifestations; therefore, genotype-first descriptions such as WT1 disorder or WT1-associated nephropathy are now often more accurate. (ratelade2010amurinemodel pages 1-2, ahmad2019theroleof pages 25-29)

Identifiers and synonyms

MONDO: MONDO:0008682, Denys–Drash syndrome. (OpenTargets Search: Denys-Drash syndrome-WT1)
OMIM: commonly indexed as Denys–Drash syndrome, 194080; the causal gene is WT1, 607102. The disease number should be independently checked against the current OMIM release before automated ingestion.
Orphanet: commonly indexed as ORPHA:220; verify against the current Orphanet release before ingestion.
MeSH: Denys-Drash Syndrome.
ICD: there is no sufficiently specific DDS code in routine ICD-10-CM; cases are generally represented using component codes for congenital malformation/DSD, nephrotic syndrome or kidney failure, and Wilms tumor. ICD-11 terminology should likewise be verified in the implementation being used.
Synonyms: Drash syndrome; Denys–Drash syndrome; DDS; WT1-related Denys–Drash syndrome; nephropathy–Wilms tumor–genital anomaly syndrome.

The evidence base is principally aggregated disease resources, small retrospective cohorts, registries, individual clinical cases, tumor series, and engineered models—not population-scale EHR epidemiology.

2. Etiology and risk factors

Primary cause

DDS is caused chiefly by a heterozygous germline WT1 pathogenic variant. Classic DDS variants are missense substitutions in exons 8 or 9, which encode zinc fingers 2 and 3 of the DNA-binding domain. Historical molecular series found WT1 variants in 10/17 and 6/8 clinically diagnosed patients, illustrating both the central role of WT1 and the limitations of early testing methods. (ahmad2019theroleof pages 25-29)

Most cases are sporadic and presumed or demonstrated de novo. A person carrying a pathogenic variant has an autosomal-dominant transmission risk of 50% for each pregnancy, although reproductive fitness may be reduced by severe childhood disease or gonadal dysgenesis.

Variant and phenotype considerations

Classic DDS: predominantly zinc-finger missense variants, often in exons 8–9. Recurrent substitutions include variants affecting Arg394, such as p.Arg394Trp in the historical numbering used by the mouse-model literature. (ratelade2010amurinemodel pages 1-2)
Frasier syndrome: classically intron 9 donor-region variants that alter the +KTS/−KTS splice-isoform ratio; usually later nephropathy, FSGS, 46,XY gonadal dysgenesis, and gonadoblastoma risk, with a lower Wilms-tumor risk than classic DDS.
Truncating/deletion variants: may produce Wilms tumor predisposition, nephropathy, genital anomalies, or overlapping phenotypes. Thus, variant class predicts risk imperfectly.
Population frequency: fully penetrant classic DDS variants should be absent or exceptionally rare in reference populations such as gnomAD. Variant-specific gnomAD and ClinVar records must nevertheless be checked individually.

Open Targets also reports low-scoring associations with GPC3 and WTIP, but these should not be encoded as established primary DDS genes. GPC3 is relevant to an overlapping Wilms-tumor/overgrowth differential, and WTIP is biologically connected to WT1/podocyte pathways; WT1 remains the definitive causal gene. (OpenTargets Search: Denys-Drash syndrome-WT1)

Environmental, protective, and gene–environment factors

No toxin, lifestyle exposure, nutritional factor, or infectious agent is established as a cause of DDS. No reproducible protective allele or environmental exposure is known to prevent expression of a pathogenic WT1 variant. Clinical severity may be affected by general modifiers of kidney injury—blood pressure, infections, nephrotoxins, and treatment—but these are downstream modifiers rather than causes. Formal DDS-specific gene–environment studies are lacking.

3. Phenotypes

Phenotype	Type and usual course	Suggested HPO term
Proteinuria	Laboratory abnormality; congenital, infantile, or early childhood; persistent and progressive	HP:0000093
Nephrotic syndrome	Clinical/laboratory syndrome with heavy proteinuria, hypoalbuminemia, and edema; generally steroid resistant	HP:0000100; HP:0003073 hypoalbuminemia; HP:0000969 edema
Diffuse mesangial sclerosis	Biopsy manifestation; severe and progressive, often leading to kidney failure before age five	HP:0005567
Chronic kidney disease/kidney failure	Progressive renal impairment; often early childhood	HP:0012622; HP:0003774
Wilms tumor/nephroblastoma	Renal malignancy, commonly early childhood; may be unilateral or bilateral/multifocal	HP:0002667
Ambiguous or undervirilized genitalia	Congenital physical manifestation in some 46,XY individuals	HP:0000062/HP:0000830, subject to HPO-release verification
Gonadal dysgenesis/streak gonads	Congenital reproductive phenotype, most relevant in 46,XY individuals	HP:0000133; HP:0000140
Hypertension	Secondary renal sign; frequency increases with progressive CKD	HP:0000822
Hematuria	Possible urinary abnormality, less defining than proteinuria	HP:0000790

The most reproducible timing statement is that DMS-associated renal disease begins in infancy or early childhood and commonly progresses to end-stage kidney disease before age five. (ratelade2010amurinemodel pages 1-2) Exact percentages for each triad component vary markedly with ascertainment and variant class; historical statements that nearly all DDS patients develop Wilms tumor should not be applied to all molecularly diagnosed WT1-nephropathy patients. (ahmad2019theroleof pages 25-29)

Quality of life. No validated DDS-specific EQ-5D, SF-36, PROMIS, or utility dataset was identified. Expected burdens include edema and dietary/fluid restrictions, frequent laboratory and imaging visits, dialysis, major surgery, cancer treatment, transplantation and immunosuppression, fertility concerns, and psychosocial effects of DSD care. These impacts are clinically compelling but inadequately quantified in DDS-specific cohorts.

4. Genetic and molecular information

Gene: WT1, chromosome 11p13; HGNC:12796; NCBI Gene:7490; OMIM gene entry 607102.
Protein: WT1 transcription factor, a nuclear zinc-finger DNA/RNA-binding regulator with multiple isoforms, notably +KTS and −KTS.
Origin: usually constitutional germline; a second somatic alteration or other cooperating event can occur in tumor tissue. A germline result should not be confused with tumor-only somatic WT1 alteration.
Mechanism: classic zinc-finger missense variants impair sequence-specific DNA binding and may exert dominant-negative effects on wild-type WT1. Mouse evidence also supports a dosage or threshold model in which residual normal WT1 activity determines podocyte stability. (ratelade2010amurinemodel pages 1-2)
Classification: recurrent zinc-finger variants with established DDS cases are generally pathogenic/likely pathogenic; novel variants require ACMG/AMP assessment using population rarity, de novo status, phenotype specificity, functional evidence, and segregation. A VUS alone does not establish DDS.
Chromosomal abnormalities: larger 11p13 deletions involving WT1 cause WAGR-spectrum disease rather than classic DDS. Karyotype or chromosomal microarray is useful when syndromic features suggest a deletion, but most classic DDS cases have sequence-level variants.
Modifier genes/epigenetics: no clinically validated modifier gene or DDS-specific constitutional epigenetic signature is established. Tumor evolution may involve additional genetic and epigenetic events, but these are not diagnostic of the constitutional syndrome.

5. Environmental information

Environmental toxins, radiation, smoking, alcohol, diet, occupation, and infectious agents are not recognized initiating factors. Avoiding nephrotoxins, controlling blood pressure, maintaining appropriate nutrition, and preventing infection are tertiary renal-care measures, not primary prevention of DDS. There is no zoonotic or transmissible component.

6. Mechanism and pathophysiology

Ordered causal chain

A heterozygous germline WT1 pathogenic variant leads to reduced or qualitatively abnormal WT1 transcription-factor activity in developing renal and gonadal tissues.
Abnormal WT1 activity leads to impaired regulation of nephron-progenitor renewal, mesenchymal-to-epithelial transition, and podocyte differentiation/maintenance.
Impaired podocyte programs lead to altered slit-diaphragm, actin-cytoskeleton, focal-adhesion, polarity, and paracrine angiogenic/growth-factor signaling.
Podocyte dysfunction results in filtration-barrier failure, heavy proteinuria, and nephrotic syndrome.
Continued podocyte and mesangial injury leads to DMS/glomerulosclerosis, nephron loss, CKD, and early kidney failure.
Branch A: defective WT1-dependent sex determination and gonadal development leads to 46,XY gonadal dysgenesis and undervirilized/ambiguous external genitalia.
Branch B: constitutional loss of WT1 tumor-suppressor competence plus additional renal-cell events—this second-event sequence is partly inferred and varies by tumor—leads to nephrogenic precursor persistence and Wilms tumor.

Molecular and cellular detail

WT1 regulates FGF and BMP–pSMAD signaling, the developmental regulators SALL1 and PAX2, and mesenchymal-to-epithelial transition through FGF8 and WNT4. In podocytes, WT1 helps establish identity through MAFB, LMX1B, FOXC2, and TCF21, coordinating cytoskeletal, slit-diaphragm, polarity, and basement-membrane attachment programs. These relationships derive substantially from developmental and model evidence and should therefore be annotated as mechanistic support rather than direct proof in every human DDS kidney. (ratelade2010amurinemodel pages 1-2)

The p.Arg394Trp knock-in mouse developed DMS-like disease and early renal failure and revealed altered glomerular expression of candidate WT1 targets including Scel, Sulf1, and Cyp26a1. The authors described the work as providing insight into “early mechanisms leading to glomerular” disease and concluded that the results support a threshold/dominant-negative model of WT1 function. (ratelade2010amurinemodel pages 1-2)

Suggested annotations

Biological processes: GO:0072006 nephron development; GO:0032835 glomerulus development; GO:0006355 regulation of DNA-templated transcription; GO:0007275 multicellular organism development; mesenchymal-to-epithelial transition and kidney epithelium development terms should be release-checked.
Molecular function: GO:0003700 DNA-binding transcription-factor activity; GO:0000976 transcription cis-regulatory-region binding.
Cell types: CL:0000653 podocyte; CL:0000099 mesangial cell; nephron progenitor cell and gonadal supporting-cell terms should be checked against the current CL release.
Cellular component: GO:0005634 nucleus; GO:0005923 bicellular tight junction is not a precise substitute for the slit diaphragm, so a current slit-diaphragm term should be used where available.

No validated DDS metabolomic or lipidomic diagnostic signature exists. Human single-cell/spatial studies specifically resolving classic DDS remain emerging; consequently, most current cell-state conclusions come from engineered models, bulk glomerular profiling, and podocyte culture rather than large human single-cell cohorts.

7. Anatomical structures affected

Primary: kidneys (UBERON:0002113), renal glomeruli (UBERON:0001285), podocytes, mesangial compartment, and developing nephrogenic tissue.
Genital/reproductive: gonads (UBERON:0000473), testes or dysgenetic/streak gonads, and internal/external genital structures in 46,XY DSD.
Tumor site: one or both kidneys; bilateral or multifocal disease can occur in predisposition syndromes.
Subcellular: WT1 acts primarily in the nucleus (GO:0005634); downstream dysfunction affects the podocyte actin cytoskeleton, cell–matrix adhesions, and slit diaphragm.

DMS is intrinsically diffuse and generally bilateral at the glomerular level. Wilms tumor, by contrast, can be unilateral, bilateral, or multifocal.

8. Temporal development

The constitutional lesion is present from conception, while phenotypic expression is developmental and age dependent. Genital differences are congenital. Proteinuria/nephrotic syndrome usually becomes evident congenitally, in infancy, or early childhood. DMS progresses chronically and often rapidly to kidney failure before age five. (ratelade2010amurinemodel pages 1-2)

A French transplant-study protocol reports a median kidney-transplant age of 3.6 years, consistent with aggressive early renal progression. (NCT07605884 chunk 1) There is no spontaneous renal remission in established DMS; apparent pharmacologic responses in isolated reports should not be generalized. The critical intervention window is therefore before irreversible kidney failure or advanced tumor development: prompt WT1 testing, renal monitoring, tumor surveillance, and multidisciplinary planning.

9. Inheritance and population

DDS is autosomal dominant but commonly de novo. Penetrance is high for some WT1-associated phenotype, but penetrance of each individual component—DMS, Wilms tumor, or DSD—is incomplete and variant dependent. Expressivity is substantial, even among people grouped under WT1-related disease. Genetic anticipation is not recognized. Parental germline mosaicism is possible even when parental blood tests are negative, but its frequency is unknown.

No credible population prevalence, annual incidence, carrier frequency, founder effect, ethnic enrichment, or consanguinity effect was identified. DDS occurs worldwide and across ancestry groups. Apparent sex ratios depend on whether sex is classified by chromosomes, gonads, phenotype, or sex assignment; DSD ascertainment particularly enriches reported 46,XY cases. The disease is too rare and inconsistently defined historically for a robust cases-per-100,000 estimate.

10. Diagnostics

Recommended approach

Recognize the phenotype: early steroid-resistant nephrotic syndrome, DMS, Wilms tumor at a young age, bilateral/multifocal Wilms tumor, or unexplained 46,XY DSD.
Renal evaluation: urinalysis and urine protein/creatinine ratio; serum albumin, creatinine/eGFR, electrolytes; blood pressure; edema and nutritional assessment.
Imaging: renal ultrasonography to assess tumor, nephrogenic rests, kidney size, and structural disease. MRI is preferred when more detailed tumor characterization is needed without ionizing radiation.
Pathology: biopsy typically shows DMS—mesangial-matrix expansion and sclerosis involving glomeruli—although biopsy can be avoided when genetic and clinical evidence is definitive or procedural risk is excessive.
Molecular confirmation: sequence and deletion/duplication analysis of WT1. A comprehensive steroid-resistant nephrotic syndrome/Wilms-predisposition panel is appropriate when the phenotype is atypical.
DSD evaluation: chromosome analysis or rapid sex-chromosome assessment, pelvic/abdominal imaging, gonadal and adrenal hormone testing as clinically indicated, and multidisciplinary endocrinology/urology/genetics review.
Tumor genetics: paired germline/tumor analysis can clarify constitutional predisposition and acquired tumor events but is not required to diagnose nephropathy.

WES/WGS. Exome or genome sequencing is useful if targeted testing is negative, if the phenotype overlaps another monogenic podocytopathy, or if structural/noncoding variation is suspected. Genome sequencing may better detect complex structural and selected intronic variants, but targeted WT1 analysis remains efficient for a classic presentation.

CMA/karyotype/FISH. CMA is appropriate for suspected 11p13 deletion/WAGR. Karyotype is important for DSD assessment. FISH has a limited confirmatory role. Mitochondrial and repeat-expansion testing are not routine DDS tests.

Differential diagnosis: Frasier syndrome and other WT1-related nephropathies; WAGR; isolated DMS; NPHS1/NPHS2/LAMB2/PLCE1 and other genetic nephrotic syndromes; Simpson–Golabi–Behmel syndrome; Beckwith–Wiedemann spectrum; sporadic Wilms tumor; and other causes of 46,XY DSD. Distinction increasingly rests on molecular diagnosis rather than requiring the complete historical triad.

11. Outcome and prognosis

Untreated nephropathy is progressive and typically culminates in childhood kidney failure. Long-term morbidity arises from dialysis, transplantation, tumor therapy, hypertension, CKD-mineral/bone disease, growth impairment, gonadal dysfunction, infertility, and psychosocial effects. DDS-specific five- and ten-year survival estimates were not found and should not be inferred from general Wilms-tumor survival statistics.

Kidney transplantation can provide durable renal replacement because the intrinsic podocytopathy does not usually recur in a genetically normal graft. However, tumor status and native-kidney management must be addressed first. A current French observational protocol cites 20% PTLD risk in DDS recipients versus approximately 4% in general transplant populations, and a median transplantation age of 3.6 years; these figures are cohort/protocol observations, not universal rates. (NCT07605884 chunk 1)

Prognosis depends on variant class, age and rate of renal decline, Wilms-tumor stage/histology and bilaterality, treatment toxicity, DSD/gonadal-tumor issues, transplantation access, and post-transplant complications. No validated molecular prognostic score exists.

12. Treatment and current applications

There is no approved therapy that corrects WT1 dysfunction.

Renal management

Salt/fluid management, individualized nutrition, edema treatment, vaccination, and blood-pressure control.
ACE-inhibitor or angiotensin-receptor-blocker therapy may reduce proteinuria when blood pressure, kidney function, and potassium permit; these are supportive rather than curative.
Genetic DMS is generally steroid resistant. Prolonged empiric glucocorticoids or other immunosuppression should be avoided once a monogenic WT1 podocytopathy is established unless another indication exists.
Dialysis is used for kidney failure or as a bridge to transplantation.
Unilateral or bilateral nephrectomy is individualized according to tumor status, severe protein loss/hypertension, residual function, and transplant planning.
Kidney transplantation is definitive renal replacement after oncologic assessment; genetic disease recurrence in the graft is not expected.

Suggested NCIT interventions: Angiotensin-Converting Enzyme Inhibitor, Angiotensin Receptor Blocker, Dialysis, Nephrectomy, and Kidney Transplantation; exact NCIT codes should be release-validated.

Wilms tumor and DSD management

Wilms tumor is treated according to pediatric oncology risk, stage, histology, laterality, and cooperative-group protocol, using surgery plus chemotherapy, with radiotherapy for selected risk groups. Nephron-sparing strategies are particularly important for bilateral disease but must be balanced against oncologic control and already progressive DMS.

DSD management requires pediatric endocrinology, urology/surgery, genetics, psychology, nephrology, oncology, and ethics expertise. Gonadal management is individualized according to gonadal location/function, malignancy risk, the person’s values, and contemporary DSD standards; irreversible procedures should not be reduced to the older diagnosis label alone.

Experimental therapy and trials

No DDS-specific gene therapy, CRISPR, RNA therapy, cell therapy, or targeted pharmacologic intervention was identified in clinical trials. Current real-world research is observational:

NCT01252901: WT1-mutation-associated disease registry; completed; 52 participants.
NCT06065852: UK National Registry of Rare Kidney Diseases; recruiting; target enrollment 35,000.
NCT01793168: rare-disease registry/natural-history study; recruiting; target enrollment 20,000.
NCT07605884: planned 108-participant observational case-control study of PTLD risk after transplantation in DDS. The protocol analyzes French data from 2000–2022. (NCT07605884 chunk 1)

These studies support natural-history and safety characterization but do not establish treatment efficacy.

13. Prevention

Primary prevention: no lifestyle or vaccine can prevent a de novo WT1 variant. Reproductive options after identification of a familial variant include genetic counseling, prenatal diagnosis, and IVF with preimplantation genetic testing for monogenic disease.

Secondary prevention: molecular diagnosis, cascade testing, renal monitoring, and Wilms-tumor surveillance can identify complications earlier. Common expert practice is renal ultrasonography approximately every three months through the principal childhood risk window, but the exact stopping age and protocol should follow the responsible cancer-predisposition guideline and variant-specific risk assessment rather than an unreferenced universal rule.

Tertiary prevention: aggressive CKD and hypertension management; avoidance of nephrotoxins; dialysis/transplant planning; vaccination before transplantation; tumor follow-up; DSD and gonadal surveillance; and monitoring for immunosuppression-related EBV/PTLD. The PTLD signal in the French protocol makes EBV-risk assessment and post-transplant viral monitoring especially important, although the magnitude requires confirmation. (NCT07605884 chunk 1)

14. Other species and natural disease

No well-established naturally occurring veterinary DDS counterpart was identified. DDS is not infectious, transmissible, or zoonotic. WT1 orthologs and renal-development functions are evolutionarily conserved, making engineered animals scientifically useful, but this does not constitute natural disease in those species.

15. Model organisms and advanced research

The most informative system is Mus musculus (NCBI Taxon:10090). Knock-in mice carrying the DDS-associated Wt1 p.Arg394Trp allele reproduce key renal features, including podocyte dysfunction, DMS/glomerulosclerosis, proteinuria, and early renal failure. Isolated-glomerulus expression profiling identified Scel, Sulf1, and Cyp26a1 as altered candidate WT1 targets. This is strong causal model evidence, although timing, genetic background, and complete tumor/DSD penetrance differ from human disease. (ratelade2010amurinemodel pages 1-2)

Additional models include Wt1 hypomorphic, knockout/conditional-knockout, and truncating-allele mice; immortalized human podocytes derived from DDS patients; transfected podocyte systems for DNA-binding/localization assays; and kidney organoids or iPSC systems as emerging platforms. Patient-podocyte proteomics and model transcriptomics indicate dedifferentiation and cytoskeletal/signaling abnormalities, but no proteomic, metabolomic, or epigenomic signature is clinically validated.

Recent developments and expert assessment

The major 2023–2024 conceptual development is the move from rigid eponymous categories toward a WT1-related disorder spectrum, integrating genotype, age at nephropathy, histology, DSD, and tumor risk. A 2024 review, WT1-related disorders: more than Denys–Drash syndrome, reflects this shift (López-González and Ariceta, Pediatric Nephrology, published online February 2024; DOI: https://doi.org/10.1007/s00467-024-06302-y). A 2024 review of developmental FSGS likewise emphasizes genetically defined podocytopathies and transplantation rather than treating the biopsy pattern as a stand-alone disease (Klomp et al., March 2024; DOI: https://doi.org/10.1159/000538345).

The practical expert interpretation is that DDS should be considered a high-risk clinical presentation of germline WT1 dysfunction, not a diagnosis requiring every element of the classic triad. Early genomic diagnosis can prevent ineffective immunosuppression, trigger tumor and DSD evaluation, guide family counseling, and permit coordinated oncologic and transplant planning. This interpretation is consistent with the strong WT1–DDS association and with model evidence connecting defective WT1 dosage/function directly to podocyte failure. (OpenTargets Search: Denys-Drash syndrome-WT1, ratelade2010amurinemodel pages 1-2)

Key evidence quotations and references

Ratelade et al., 2010, Human Molecular Genetics. DOI: https://doi.org/10.1093/hmg/ddp462. The study describes DDS as involving “early-onset nephrotic syndrome, male pseudohermaphroditism, and Wilms tumor predisposition,” reports that DMS generally reaches renal failure before age five, and provides p.Arg394Trp mouse-model evidence for a WT1 activity-threshold/dominant-negative mechanism. (ratelade2010amurinemodel pages 1-2)
Historical human genetics summarized in the retrieved literature: Pelletier et al. identified WT1 variants in 10/17 DDS patients, while Baird et al. detected heterozygous germline variants in 6/8; the characteristic lesions clustered in exons 8–9. (ahmad2019theroleof pages 25-29)
Open Targets, accessed through the research tool: WT1 had five disease-evidence records and an association score of 0.853 for MONDO:0008682, far exceeding GPC3 or WTIP. Supporting PubMed records listed by the resource include PMID 1302008, 1658787, 1655284, 1327525, 8388765, 10571943, 9499425, 9529364, 9607189, 11182928, and 24402088. (OpenTargets Search: Denys-Drash syndrome-WT1)
NCT07605884, ClinicalTrials.gov, 2026 protocol record. The study reports a French-cohort signal of 20% PTLD in DDS transplant recipients versus 4% in general transplant populations and median transplant age 3.6 years; these data require prospective or independent confirmation. (NCT07605884 chunk 1)

Evidence limitations

DDS is exceptionally rare, historical clinical definitions are inconsistent, and modern molecular cohorts often combine DDS, Frasier syndrome, isolated WT1 nephropathy, and other WT1 disorders. Consequently, many commonly repeated penetrance and tumor-risk percentages are ascertainment-sensitive. Recent 2023–2024 sources are mainly expert reviews rather than DDS-specific prospective cohorts. No randomized therapeutic trial, validated quality-of-life instrument, robust population incidence estimate, DDS-specific multi-omics diagnostic signature, or clinically established disease-modifying therapy was identified.

References

(OpenTargets Search: Denys-Drash syndrome-WT1): Open Targets Query (Denys-Drash syndrome-WT1, 3 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(ratelade2010amurinemodel pages 1-2): Julien Ratelade, Christelle Arrondel, Ghislaine Hamard, Serge Garbay, Scott Harvey, Nathalie Biebuyck, Herbert Schulz, Nick Hastie, Marco Pontoglio, Marie-Claire Gubler, Corinne Antignac, and Laurence Heidet. A murine model of denys-drash syndrome reveals novel transcriptional targets of wt1 in podocytes. Human molecular genetics, 19 1:1-15, Sep 2010. URL: https://doi.org/10.1093/hmg/ddp462, doi:10.1093/hmg/ddp462. This article has 50 citations and is from a domain leading peer-reviewed journal.
(ahmad2019theroleof pages 25-29): AH Bin Ahmad. The role of wt1 in nephron endowment and glomeruloscerosis (gs)/chronic kidney disease (ckd). Unknown journal, 2019.
(NCT07605884 chunk 1): Denys-Drash Syndrome and Risk of Post-transplant Lymphoproliferative Disorder. Assistance Publique - Hôpitaux de Paris. 2026. ClinicalTrials.gov Identifier: NCT07605884

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	0
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	38
Resolved	34
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	4
Terms whose name was checked	8
Terms named correctly	0
Terms named as a different term	6
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0000093 (2 mentions) - the report calls it "Laboratory abnormality; congenital, infantile, or early childhood; persistent and progressive"; HP calls it Proteinuria
HP:0005567 (2 mentions) - the report calls it "Biopsy manifestation; severe and progressive, often leading to kidney failure before age five"; HP calls it Renal magnesium wasting
HP:0002667 (2 mentions) - the report calls it "Renal malignancy, commonly early childhood; may be unilateral or bilateral/multifocal"; HP calls it Nephroblastoma
GO:0005634 (3 mentions) - the report calls it "Subcellular: WT1 acts primarily in the nucleus"; GO calls it nucleus**
HP:0000822 (1 mention) - the report calls it "Secondary renal sign; frequency increases with progressive CKD"; HP calls it Hypertension
HP:0000790 (1 mention) - the report calls it "Possible urinary abnormality, less defining than proteinuria"; HP calls it Hematuria

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

UBERON:0002113 (2 mentions) - the report calls it "Primary: kidneys"; UBERON calls it kidney**, and lists "reniculate kidney" among its other names
UBERON:0000473 (2 mentions) - the report calls it "Genital/reproductive: gonads"; UBERON calls it testis**, and lists "gonad of male reproductive system" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Taxon, ORPHA, Gene.

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Denys–Drash Syndrome: Disease-Characteristics Research Report

Executive summary

1. Disease information

2. Etiology and risk factors

Primary cause

Variant and phenotype considerations

Environmental, protective, and gene–environment factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Molecular and cellular detail

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended approach

11. Outcome and prognosis

12. Treatment and current applications

Renal management

Wilms tumor and DSD management

Experimental therapy and trials

13. Prevention

14. Other species and natural disease

15. Model organisms and advanced research

Recent developments and expert assessment

Key evidence quotations and references

Evidence limitations

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver