WAGR Syndrome - dismech

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Subtypes

2

WAGR syndrome (BDNF intact)

Classic WAGR syndrome with an 11p13 deletion encompassing WT1 and PAX6 but sparing BDNF. Affected individuals show Wilms tumor predisposition, aniridia, genitourinary anomalies, and a range of developmental delay without the severe childhood-onset obesity characteristic of the WAGRO subtype.

WAGRO syndrome (BDNF-deleted)

Extended-deletion subtype in which the 11p deletion reaches distally to include BDNF at 11p14.1. BDNF haploinsufficiency adds hyperphagia and childhood-onset Obesity to the WAGR phenotype, giving the WAGRO acronym.

Show evidence (1 reference)

PMID:23266638 SUPPORT Human Clinical

"are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome)"

Defines the WAGRO subtype as WAGR plus obesity arising from extension of the deletion to include BDNF.

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Pathophysiology

4

11p13 contiguous-gene deletion

WAGR syndrome results from a heterozygous, variably sized interstitial deletion at chromosome 11p13 that simultaneously removes multiple contiguous genes, obligately including WT1 and PAX6. Because the deletion is the unifying lesion, the specific genes lost (and therefore the clinical features) depend on deletion extent; larger deletions reaching BDNF produce the WAGRO obesity subphenotype.

Downstream

WT1 haploinsufficiency and Wilms tumor predisposition The 11p13 deletion obligately removes one WT1 allele, producing WT1 haploinsufficiency.

PAX6 haploinsufficiency and ocular maldevelopment The 11p13 deletion obligately removes one PAX6 allele, producing PAX6 haploinsufficiency.

BDNF haploinsufficiency and hypothalamic energy dysregulation When the deletion extends distally to BDNF, one BDNF allele is lost, producing BDNF haploinsufficiency (WAGRO subtype).

Show evidence (3 references)

PMID:41818601 SUPPORT Human Clinical

"a deletion of chromosome 11p13 that includes the genes WT1 and PAX6 identified by molecular genetic testing"

The GeneReviews diagnostic criterion confirms that a contiguous 11p13 deletion removing both WT1 and PAX6 defines the disorder.

PMID:18753648 SUPPORT Human Clinical

"Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13"

Confirms the contiguous-gene deletion mechanism and the variability in deletion size that underlies the phenotypic spectrum.

PMID:34970513 SUPPORT Human Clinical

"a broader phenotypic spectrum beyond the classic syndrome exists"

Registry data support reframing the contiguous-deletion disorder as a broad WAGR spectrum whose manifestations depend on the genes deleted.

WT1 haploinsufficiency and Wilms tumor predisposition

Loss of one WT1 allele removes a copy of the WT1 zinc-finger transcription factor that is essential for normal nephrogenesis and gonadal development. Haploinsufficiency, with subsequent somatic second hits in renal blastemal cells, predisposes to Wilms tumor and contributes to genitourinary malformations and later glomerular/kidney dysfunction.

nephrogenic blastemal cell CL:0000354 podocyte CL:0000653

WT1 hgnc:12796

kidney development GO:0001822 ↓ DECREASED gonad development GO:0008406 ⚠ ABNORMAL

Downstream

Nephroblastoma WT1 haploinsufficiency with somatic second hits predisposes to Wilms tumor.

Genital anomalies WT1 haploinsufficiency disrupts genital development, causing genital anomalies including cryptorchidism.

Congenital anomalies of the kidney and urinary tract WT1 haploinsufficiency disrupts kidney and urinary tract development, causing congenital anomalies of the kidney and urinary tract.

Renal failure WT1-associated nephropathy and the renal consequences of Wilms tumor can progress to kidney failure.

Show evidence (1 reference)

PMID:18753648 SUPPORT Human Clinical

"haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13"

WT1 haploinsufficiency in the contiguous deletion is the basis of the Wilms tumor and genitourinary components of WAGR syndrome.

PAX6 haploinsufficiency and ocular maldevelopment

Loss of one PAX6 allele reduces dosage of the PAX6 master transcription factor that controls eye morphogenesis. Haploinsufficiency causes classic aniridia together with a pan-ocular phenotype affecting the cornea, lens, anterior segment, fovea, and optic nerve, as well as central nervous system features.

PAX6 hgnc:8620

camera-type eye development GO:0043010 ⚠ ABNORMAL iris morphogenesis GO:0061072 ↓ DECREASED

Downstream

Aniridia PAX6 haploinsufficiency causes classic aniridia.

Cataract PAX6 haploinsufficiency contributes to the pan-ocular phenotype including cataract.

Glaucoma PAX6-related anterior-segment dysgenesis raises intraocular pressure, causing glaucoma.

Nystagmus Foveal hypoplasia and aniridia from PAX6 loss produce nystagmus.

Foveal hypoplasia PAX6 haploinsufficiency impairs foveal development, causing foveal hypoplasia.

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"Classic aniridia affects the iris (partial or full iris hypoplasia), cornea (corneal keratopathy), anterior segment"

GeneReviews documents that PAX6 dosage loss produces the pan-ocular aniridia phenotype seen in WAGR syndrome.

BDNF haploinsufficiency and hypothalamic energy dysregulation

When the 11p deletion extends distally to BDNF (11p14.1), brain-derived neurotrophic factor dosage is reduced. BDNF acts in hypothalamic circuits regulating energy homeostasis, and its haploinsufficiency produces hyperphagia and childhood-onset obesity, defining the WAGRO subtype. Serum BDNF is roughly halved in deletion carriers. Because BDNF also regulates CNS development and synaptic plasticity, its haploinsufficiency additionally contributes to more severe cognitive and adaptive-behavior impairment within WAGR syndrome.

BDNF hgnc:1033

regulation of feeding behavior GO:0060259 ⚠ ABNORMAL regulation of synaptic plasticity GO:0048167 ⚠ ABNORMAL

Downstream

Hyperphagia BDNF haploinsufficiency dysregulates hypothalamic energy balance, producing hyperphagia.

Childhood-onset obesity BDNF-driven hyperphagia and impaired energy homeostasis produce childhood-onset obesity in the WAGRO subtype.

Autism spectrum disorder BDNF haploinsufficiency impairs CNS development and is associated with higher rates of autistic features.

Show evidence (3 references)

PMID:18753648 SUPPORT Human Clinical

"BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity"

Han et al. directly link BDNF haploinsufficiency to reduced serum BDNF and obesity in WAGR patients, establishing the WAGRO mechanism.

PMID:18753648 SUPPORT Human Clinical

"The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF"

Maps the obesity-critical region to BDNF, supporting the dosage mechanism for the WAGRO phenotype.

PMID:23517654 SUPPORT Human Clinical

"among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects"

Demonstrates that BDNF haploinsufficiency within WAGR syndrome lowers adaptive behavior and cognition, extending the BDNF dosage mechanism to neurocognitive outcomes.

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Pathograph

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Phenotypes

18

Eye 4

Aniridia Aniridia HP:0000526

Show evidence (1 reference)

PMID:16199712 SUPPORT Human Clinical

"clinically associated with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation"

The 54-case clinical review lists aniridia as a cardinal feature of WAGR syndrome.

Cataract Cataract HP:0000518

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"lens (cataract and lens subluxation)"

Cataract is part of the PAX6 aniridia syndrome ocular spectrum that applies to WAGR aniridia.

Glaucoma Glaucoma HP:0000501

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"anterior segment (resulting in raised intraocular pressure and glaucoma)"

Glaucoma is documented in the PAX6 aniridia ocular phenotype relevant to WAGR.

Nystagmus Nystagmus HP:0000639

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"Individuals with classic aniridia characteristically show nystagmus and impaired visual acuity"

Nystagmus is a characteristic feature of classic aniridia, which is part of WAGR syndrome.

Genitourinary 4

Nephroblastoma FREQUENT Nephroblastoma HP:0002667

Show evidence (2 references)

PMID:16199712 SUPPORT Human Clinical

"clinically associated with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation"

Wilms tumor is the "W" of WAGR and a cardinal feature documented in the clinical review.

PMID:33146894 SUPPORT Human Clinical

"WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT)"

Quantifies the high (45-60%) lifetime Wilms tumor risk in WAGR syndrome, supporting FREQUENT frequency and the need for renal surveillance.

Genital anomalies Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:16199712 SUPPORT Human Clinical

"clinically associated with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation"

Genitourinary anomalies (the "G" of WAGR) are a cardinal feature; cryptorchidism is a common genital manifestation.

Congenital anomalies of the kidney and urinary tract Abnormality of the urinary system HP:0000079

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"genital anomalies and congenital anomalies of the kidney and urinary tract"

GeneReviews documents congenital anomalies of the kidney and urinary tract among the urologic manifestations of WAGR spectrum disorder.

Renal failure Renal insufficiency HP:0000083

Show evidence (1 reference)

PMID:34970513 SUPPORT Human Clinical

"patients affected by WAGR syndrome can develop obesity and kidney failure"

The WAGR patient registry documents kidney failure as a recognized manifestation of the WAGR spectrum.

Immune 1

Recurrent infections Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"hypotonia and scoliosis, and recurrent infections"

GeneReviews lists recurrent infections among the expanded WAGR spectrum findings.

Musculoskeletal 2

Hypotonia Hypotonia HP:0001252

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"hypotonia and scoliosis, and recurrent infections"

GeneReviews lists hypotonia among the expanded WAGR spectrum findings.

Scoliosis Scoliosis HP:0002650

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"hypotonia and scoliosis, and recurrent infections"

GeneReviews lists scoliosis among the expanded WAGR spectrum findings.

Nervous System 5

Intellectual disability Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:24357251 SUPPORT Human Clinical

"Developmental delay and autistic features are major complications of this syndrome"

Developmental delay/intellectual disability is documented as a major complication of WAGR syndrome.

Hyperphagia Polyphagia HP:0002591

Show evidence (1 reference)

PMID:18753648 SUPPORT Human Clinical

"Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome"

Hyperphagia is reported in the obesity-prone subgroup of WAGR patients (the WAGRO subtype with BDNF deletion).

Autism spectrum disorder Autism HP:0000717

Show evidence (1 reference)

PMID:24357251 SUPPORT Human Clinical

"the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down"

Autistic features are documented as a major complication and were genetically mapped within the WAGR critical region.

Attention deficit hyperactivity disorder Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"attention-deficit/hyperactivity disorder (ADHD)"

GeneReviews lists ADHD among the neurobehavioral/psychiatric manifestations of PAX6 aniridia syndrome, which applies to WAGR syndrome.

Anxiety Anxiety HP:0000739

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"mood disorders such as depression and anxiety"

GeneReviews lists anxiety among the mood-disorder manifestations of PAX6 aniridia syndrome, which applies to WAGR syndrome.

Growth 1

Childhood-onset obesity Obesity HP:0001513

Show evidence (1 reference)

PMID:18753648 SUPPORT Human Clinical

"By 10 years of age, 100% of the patients with heterozygous BDNF deletions"

All BDNF-deletion (WAGRO) patients were obese by age 10, supporting childhood-onset obesity as a subtype feature.

Other 1

Foveal hypoplasia Hypoplasia of the fovea HP:0007750

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"fovea (foveal hypoplasia)"

Foveal hypoplasia is documented in the PAX6 aniridia ocular spectrum applicable to WAGR.

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Genetic Associations

1

11p13 contiguous-gene deletion

Autosomal dominant

Show evidence (2 references)

PMID:41818601 SUPPORT Human Clinical

"WAGR spectrum disorder is an autosomal dominant disorder typically caused by a de novo 11p13 deletion"

GeneReviews establishes the autosomal dominant, usually de novo, 11p13 deletion etiology.

PMID:18753648 SUPPORT Human Clinical

"Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions"

Documents the wide range of deletion sizes and the proportion extending to BDNF.

💊

Medical Actions

6

Wilms tumor surveillance

Action: surveillance for malignancies MAXO:0001492

Routine renal imaging surveillance (e.g., abdominal/renal ultrasound on a scheduled interval through early childhood) is recommended for WAGR patients because of the high Wilms tumor risk, enabling early detection.

Show evidence (2 references)

PMID:41818601 SUPPORT Human Clinical

"Recommendations have been published regarding routinely scheduled follow up to monitor existing manifestations"

GeneReviews documents published scheduled surveillance recommendations, which include Wilms tumor monitoring given the oncologic risk.

PMID:33146894 SUPPORT Human Clinical

"intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised"

The SIOP-RTSG cohort advises ongoing surveillance of remaining kidney tissue in WAGR patients given the high rate of bilateral disease.

Wilms tumor surgical resection

Action: nephrectomy MAXO:0001065

Surgical resection of Wilms tumor (nephron-sparing surgery or nephrectomy), the surgical component of the established multimodality Wilms tumor regimen that also includes chemotherapy and risk-adapted radiation, coordinated by pediatric oncology.

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"oncology (Wilms tumor risk assessment and management)"

GeneReviews specifies pediatric oncology management of Wilms tumor risk, which includes surgical resection when tumors arise.

Wilms tumor chemotherapy

Action: chemotherapy MAXO:0000647

Chemotherapy is a core component of the multimodality Wilms tumor regimen in WAGR syndrome, given alongside surgical resection and risk-adapted radiation under pediatric oncology.

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"oncology (Wilms tumor risk assessment and management)"

GeneReviews specifies pediatric oncology management of Wilms tumor, which encompasses chemotherapy as a core element of the multimodality regimen.

Aniridia and ophthalmologic management

Action: supportive care MAXO:0000950

Multidisciplinary ophthalmologic care for complications of aniridia, including correction of refractive errors, tinted/photochromic lenses, glaucoma medication, and cautious surgical management given keratopathy and foveal hypoplasia.

Show evidence (1 reference)

PMID:20301534 SUPPORT Human Clinical

"use of topical anti-glaucoma medication to manage glaucoma when possible"

GeneReviews details ophthalmologic supportive management of aniridia complications such as glaucoma.

Developmental and behavioral support

Action: supportive care MAXO:0000950

Early childhood developmental intervention and management of intellectual disability and neurobehavioral/psychiatric issues by developmental specialists.

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"early childhood development (developmental delay / intellectual disability, neurobehavioral issues)"

GeneReviews recommends developmental and neurobehavioral support as part of multidisciplinary WAGR care.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for recurrence-risk assessment, including parental genetic and chromosome evaluation for predisposing rearrangements, with prenatal and preimplantation genetic testing options.

Show evidence (1 reference)

PMID:41818601 SUPPORT Human Clinical

"Recommended evaluations of the parents to confirm their genetic status and to allow reliable recurrence risk counseling"

GeneReviews recommends parental genetic evaluation and counseling for recurrence-risk assessment in WAGR spectrum disorder families.

{ }

Source YAML

click to show

name: WAGR Syndrome
creation_date: "2026-06-03T00:00:00Z"
category: Genetic
synonyms:
- WAGR spectrum disorder
- WAGR complex
- 11p13 deletion syndrome
- Wilms tumor-aniridia-genitourinary anomalies-intellectual disability syndrome
- WAGRO syndrome
description: >
  WAGR syndrome (WAGR spectrum disorder) is a rare contiguous-gene deletion
  disorder caused by a heterozygous interstitial deletion of chromosome band
  11p13 that removes several adjacent genes, most importantly WT1 and PAX6. The
  acronym denotes its cardinal features: Wilms tumor, Aniridia, Genitourinary
  anomalies, and a Range of neurodevelopmental delay/intellectual disability.
  WT1 haploinsufficiency predisposes to Wilms tumor (nephroblastoma), genitourinary
  malformations, and later-onset nephropathy, while PAX6 haploinsufficiency causes
  aniridia and a pan-ocular developmental phenotype. The variable size of the
  deletion explains the phenotypic spectrum: when the deletion extends distally to
  include BDNF (11p14.1), affected individuals additionally develop childhood-onset
  obesity and hyperphagia, designated the WAGRO subtype. The disorder is almost
  always due to a de novo 11p13 deletion and is inherited in an autosomal dominant
  manner. The recognized phenotype has broadened to include neurobehavioral and
  psychiatric features, hypotonia, scoliosis, respiratory and gastrointestinal
  issues, and recurrent infections.
disease_term:
  preferred_term: WAGR syndrome
  term:
    id: MONDO:0008681
    label: WAGR syndrome
parents:
- Chromosomal microdeletion syndrome
- Hereditary neoplastic syndrome
references:
- reference: PMID:41818601
  title: "WAGR Spectrum Disorder."
  tags:
  - GeneReviews
- reference: PMID:20301534
  title: "PAX6 Aniridia Syndrome."
  tags:
  - GeneReviews
has_subtypes:
- name: WAGR
  display_name: WAGR syndrome (BDNF intact)
  description: >
    Classic WAGR syndrome with an 11p13 deletion encompassing WT1 and PAX6 but
    sparing BDNF. Affected individuals show Wilms tumor predisposition, aniridia,
    genitourinary anomalies, and a range of developmental delay without the severe
    childhood-onset obesity characteristic of the WAGRO subtype.
- name: WAGRO
  display_name: WAGRO syndrome (BDNF-deleted)
  description: >
    Extended-deletion subtype in which the 11p deletion reaches distally to include
    BDNF at 11p14.1. BDNF haploinsufficiency adds hyperphagia and childhood-onset
    Obesity to the WAGR phenotype, giving the WAGRO acronym.
  evidence:
  - reference: PMID:23266638
    reference_title: "The modifier effect of the BDNF gene in the phenotype of the WAGRO syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome)"
    explanation: >
      Defines the WAGRO subtype as WAGR plus obesity arising from extension of the
      deletion to include BDNF.
pathophysiology:
- name: 11p13 contiguous-gene deletion
  description: >
    WAGR syndrome results from a heterozygous, variably sized interstitial deletion
    at chromosome 11p13 that simultaneously removes multiple contiguous genes,
    obligately including WT1 and PAX6. Because the deletion is the unifying lesion,
    the specific genes lost (and therefore the clinical features) depend on deletion
    extent; larger deletions reaching BDNF produce the WAGRO obesity subphenotype.
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a deletion of chromosome 11p13 that includes the genes WT1 and PAX6 identified by molecular genetic testing"
    explanation: >
      The GeneReviews diagnostic criterion confirms that a contiguous 11p13 deletion
      removing both WT1 and PAX6 defines the disorder.
  - reference: PMID:18753648
    reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13"
    explanation: >
      Confirms the contiguous-gene deletion mechanism and the variability in
      deletion size that underlies the phenotypic spectrum.
  - reference: PMID:34970513
    reference_title: "Results From the WAGR Syndrome Patient Registry: Characterization of WAGR Spectrum and Recommendations for Care Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a broader phenotypic spectrum beyond the classic syndrome exists"
    explanation: >
      Registry data support reframing the contiguous-deletion disorder as a broad
      WAGR spectrum whose manifestations depend on the genes deleted.
  downstream:
  - target: WT1 haploinsufficiency and Wilms tumor predisposition
    description: >
      The 11p13 deletion obligately removes one WT1 allele, producing WT1
      haploinsufficiency.
  - target: PAX6 haploinsufficiency and ocular maldevelopment
    description: >
      The 11p13 deletion obligately removes one PAX6 allele, producing PAX6
      haploinsufficiency.
  - target: BDNF haploinsufficiency and hypothalamic energy dysregulation
    description: >
      When the deletion extends distally to BDNF, one BDNF allele is lost, producing
      BDNF haploinsufficiency (WAGRO subtype).
- name: WT1 haploinsufficiency and Wilms tumor predisposition
  description: >
    Loss of one WT1 allele removes a copy of the WT1 zinc-finger transcription
    factor that is essential for normal nephrogenesis and gonadal development.
    Haploinsufficiency, with subsequent somatic second hits in renal blastemal
    cells, predisposes to Wilms tumor and contributes to genitourinary
    malformations and later glomerular/kidney dysfunction.
  gene:
    preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  cell_types:
  - preferred_term: nephrogenic blastemal cell
    term:
      id: CL:0000354
      label: blastemal cell
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: kidney development
    term:
      id: GO:0001822
      label: kidney development
    modifier: DECREASED
  - preferred_term: gonad development
    term:
      id: GO:0008406
      label: gonad development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18753648
    reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13"
    explanation: >
      WT1 haploinsufficiency in the contiguous deletion is the basis of the Wilms
      tumor and genitourinary components of WAGR syndrome.
  downstream:
  - target: Nephroblastoma
    description: >
      WT1 haploinsufficiency with somatic second hits predisposes to Wilms tumor.
    evidence:
    - reference: PMID:33146894
      reference_title: "Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT)"
      explanation: >
        The high Wilms tumor risk in WAGR is the clinical readout of WT1
        haploinsufficiency predisposing to nephroblastoma.
  - target: Genital anomalies
    description: >
      WT1 haploinsufficiency disrupts genital development, causing
      genital anomalies including cryptorchidism.
  - target: Congenital anomalies of the kidney and urinary tract
    description: >
      WT1 haploinsufficiency disrupts kidney and urinary tract development,
      causing congenital anomalies of the kidney and urinary tract.
  - target: Renal failure
    description: >
      WT1-associated nephropathy and the renal consequences of Wilms tumor can
      progress to kidney failure.
- name: PAX6 haploinsufficiency and ocular maldevelopment
  description: >
    Loss of one PAX6 allele reduces dosage of the PAX6 master transcription factor
    that controls eye morphogenesis. Haploinsufficiency causes classic aniridia
    together with a pan-ocular phenotype affecting the cornea, lens, anterior
    segment, fovea, and optic nerve, as well as central nervous system features.
  gene:
    preferred_term: PAX6
    term:
      id: hgnc:8620
      label: PAX6
  biological_processes:
  - preferred_term: camera-type eye development
    term:
      id: GO:0043010
      label: camera-type eye development
    modifier: ABNORMAL
  - preferred_term: iris morphogenesis
    term:
      id: GO:0061072
      label: iris morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classic aniridia affects the iris (partial or full iris hypoplasia), cornea (corneal keratopathy), anterior segment"
    explanation: >
      GeneReviews documents that PAX6 dosage loss produces the pan-ocular aniridia
      phenotype seen in WAGR syndrome.
  downstream:
  - target: Aniridia
    description: >
      PAX6 haploinsufficiency causes classic aniridia.
    evidence:
    - reference: PMID:20301534
      reference_title: "PAX6 Aniridia Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Classic aniridia affects the iris (partial or full iris hypoplasia)"
      explanation: >
        Classic aniridia is the direct ocular consequence of PAX6 dosage loss.
  - target: Cataract
    description: >
      PAX6 haploinsufficiency contributes to the pan-ocular phenotype including
      cataract.
  - target: Glaucoma
    description: >
      PAX6-related anterior-segment dysgenesis raises intraocular pressure, causing
      glaucoma.
  - target: Nystagmus
    description: >
      Foveal hypoplasia and aniridia from PAX6 loss produce nystagmus.
  - target: Foveal hypoplasia
    description: >
      PAX6 haploinsufficiency impairs foveal development, causing foveal hypoplasia.
- name: BDNF haploinsufficiency and hypothalamic energy dysregulation
  description: >
    When the 11p deletion extends distally to BDNF (11p14.1), brain-derived
    neurotrophic factor dosage is reduced. BDNF acts in hypothalamic circuits
    regulating energy homeostasis, and its haploinsufficiency produces hyperphagia
    and childhood-onset obesity, defining the WAGRO subtype. Serum BDNF is roughly
    halved in deletion carriers. Because BDNF also regulates CNS development and
    synaptic plasticity, its haploinsufficiency additionally contributes to more
    severe cognitive and adaptive-behavior impairment within WAGR syndrome.
  gene:
    preferred_term: BDNF
    term:
      id: hgnc:1033
      label: BDNF
  biological_processes:
  - preferred_term: regulation of feeding behavior
    term:
      id: GO:0060259
      label: regulation of feeding behavior
    modifier: ABNORMAL
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18753648
    reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity"
    explanation: >
      Han et al. directly link BDNF haploinsufficiency to reduced serum BDNF and
      obesity in WAGR patients, establishing the WAGRO mechanism.
  - reference: PMID:18753648
    reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF"
    explanation: >
      Maps the obesity-critical region to BDNF, supporting the dosage mechanism for
      the WAGRO phenotype.
  - reference: PMID:23517654
    reference_title: "Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects"
    explanation: >
      Demonstrates that BDNF haploinsufficiency within WAGR syndrome lowers adaptive
      behavior and cognition, extending the BDNF dosage mechanism to neurocognitive
      outcomes.
  downstream:
  - target: Hyperphagia
    description: >
      BDNF haploinsufficiency dysregulates hypothalamic energy balance, producing
      hyperphagia.
  - target: Childhood-onset obesity
    description: >
      BDNF-driven hyperphagia and impaired energy homeostasis produce childhood-onset
      obesity in the WAGRO subtype.
    evidence:
    - reference: PMID:18753648
      reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity"
      explanation: >
        Directly links BDNF haploinsufficiency to childhood-onset obesity.
  - target: Autism spectrum disorder
    description: >
      BDNF haploinsufficiency impairs CNS development and is associated with higher
      rates of autistic features.
    evidence:
    - reference: PMID:23517654
      reference_title: "Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised"
      explanation: >
        BDNF-deletion WAGR subjects more often met autism cut-off scores, linking BDNF
        dosage to autistic features (partial: modest significance in a small cohort).
phenotypes:
- name: Aniridia
  description: >
    Partial or complete absence/hypoplasia of the iris from PAX6 haploinsufficiency;
    a near-constant and often presenting feature of WAGR syndrome.
  phenotype_term:
    preferred_term: Aniridia
    term:
      id: HP:0000526
      label: Aniridia
  evidence:
  - reference: PMID:16199712
    reference_title: "WAGR syndrome: a clinical review of 54 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinically associated with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation"
    explanation: >
      The 54-case clinical review lists aniridia as a cardinal feature of WAGR
      syndrome.
- name: Nephroblastoma
  description: >
    Wilms tumor (nephroblastoma) predisposition driven by WT1 haploinsufficiency;
    a defining and surveillance-relevant component of the syndrome.
  phenotype_term:
    preferred_term: Nephroblastoma
    term:
      id: HP:0002667
      label: Nephroblastoma
  frequency: FREQUENT
  evidence:
  - reference: PMID:16199712
    reference_title: "WAGR syndrome: a clinical review of 54 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinically associated with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation"
    explanation: >
      Wilms tumor is the "W" of WAGR and a cardinal feature documented in the
      clinical review.
  - reference: PMID:33146894
    reference_title: "Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT)"
    explanation: >
      Quantifies the high (45-60%) lifetime Wilms tumor risk in WAGR syndrome,
      supporting FREQUENT frequency and the need for renal surveillance.
- name: Genital anomalies
  description: >
    Genital malformations including cryptorchidism, hypospadias, and ambiguous
    genitalia, related to WT1 dosage loss; the "G" of WAGR.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:16199712
    reference_title: "WAGR syndrome: a clinical review of 54 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinically associated with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation"
    explanation: >
      Genitourinary anomalies (the "G" of WAGR) are a cardinal feature; cryptorchidism
      is a common genital manifestation.
- name: Congenital anomalies of the kidney and urinary tract
  description: >
    Structural anomalies of the kidney and urinary tract (CAKUT) are part of the
    genitourinary spectrum of WAGR syndrome related to WT1 dosage loss.
  phenotype_term:
    preferred_term: Congenital anomalies of the kidney and urinary tract
    term:
      id: HP:0000079
      label: Abnormality of the urinary system
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genital anomalies and congenital anomalies of the kidney and urinary tract"
    explanation: >
      GeneReviews documents congenital anomalies of the kidney and urinary tract
      among the urologic manifestations of WAGR spectrum disorder.
- name: Intellectual disability
  description: >
    A range of neurodevelopmental delay and intellectual disability of variable
    severity; one of the cardinal WAGR features.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:24357251
    reference_title: "Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and autistic features are major complications of this syndrome"
    explanation: >
      Developmental delay/intellectual disability is documented as a major
      complication of WAGR syndrome.
- name: Childhood-onset obesity
  description: >
    Hyperphagia and early-onset obesity occurring in the WAGRO subtype when the
    deletion includes BDNF.
  subtype: WAGRO
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:18753648
    reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By 10 years of age, 100% of the patients with heterozygous BDNF deletions"
    explanation: >
      All BDNF-deletion (WAGRO) patients were obese by age 10, supporting
      childhood-onset obesity as a subtype feature.
- name: Hyperphagia
  description: >
    Excessive food intake associated with BDNF haploinsufficiency in the WAGRO
    subtype, contributing to childhood-onset obesity.
  subtype: WAGRO
  phenotype_term:
    preferred_term: Hyperphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:18753648
    reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome"
    explanation: >
      Hyperphagia is reported in the obesity-prone subgroup of WAGR patients (the
      WAGRO subtype with BDNF deletion).
- name: Autism spectrum disorder
  description: >
    Autistic behaviors and neurobehavioral features are common in WAGR syndrome,
    with the responsible region narrowed to a 1.6 Mb interval containing PAX6, WT1,
    and PRRG4.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:24357251
    reference_title: "Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down"
    explanation: >
      Autistic features are documented as a major complication and were genetically
      mapped within the WAGR critical region.
- name: Attention deficit hyperactivity disorder
  description: >
    ADHD is a recurrent neurobehavioral feature of WAGR/PAX6-related disease,
    reported in roughly a quarter of WAGR registry patients.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "attention-deficit/hyperactivity disorder (ADHD)"
    explanation: >
      GeneReviews lists ADHD among the neurobehavioral/psychiatric manifestations
      of PAX6 aniridia syndrome, which applies to WAGR syndrome.
- name: Anxiety
  description: >
    Anxiety is a common psychiatric manifestation of WAGR/PAX6-related disease,
    reported in a substantial proportion of WAGR registry patients.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mood disorders such as depression and anxiety"
    explanation: >
      GeneReviews lists anxiety among the mood-disorder manifestations of PAX6
      aniridia syndrome, which applies to WAGR syndrome.
- name: Cataract
  description: >
    Lens opacity occurring as part of the PAX6-related pan-ocular phenotype.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lens (cataract and lens subluxation)"
    explanation: >
      Cataract is part of the PAX6 aniridia syndrome ocular spectrum that applies to
      WAGR aniridia.
- name: Glaucoma
  description: >
    Raised intraocular pressure and glaucoma from anterior-segment dysgenesis in the
    PAX6-related ocular phenotype.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anterior segment (resulting in raised intraocular pressure and glaucoma)"
    explanation: >
      Glaucoma is documented in the PAX6 aniridia ocular phenotype relevant to WAGR.
- name: Nystagmus
  description: >
    Involuntary eye movements characteristically accompanying aniridia/foveal
    hypoplasia in PAX6-related disease.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with classic aniridia characteristically show nystagmus and impaired visual acuity"
    explanation: >
      Nystagmus is a characteristic feature of classic aniridia, which is part of
      WAGR syndrome.
- name: Foveal hypoplasia
  description: >
    Underdevelopment of the fovea contributing to impaired visual acuity in
    PAX6-related aniridia.
  phenotype_term:
    preferred_term: Foveal hypoplasia
    term:
      id: HP:0007750
      label: Hypoplasia of the fovea
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fovea (foveal hypoplasia)"
    explanation: >
      Foveal hypoplasia is documented in the PAX6 aniridia ocular spectrum applicable
      to WAGR.
- name: Recurrent infections
  description: >
    Recurrent infections are among the expanded phenotypic features of WAGR spectrum
    disorder.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia and scoliosis, and recurrent infections"
    explanation: >
      GeneReviews lists recurrent infections among the expanded WAGR spectrum
      findings.
- name: Hypotonia
  description: >
    Reduced muscle tone reported among the expanded WAGR spectrum features.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia and scoliosis, and recurrent infections"
    explanation: >
      GeneReviews lists hypotonia among the expanded WAGR spectrum findings.
- name: Scoliosis
  description: >
    Abnormal lateral curvature of the spine reported among the expanded WAGR
    spectrum features.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia and scoliosis, and recurrent infections"
    explanation: >
      GeneReviews lists scoliosis among the expanded WAGR spectrum findings.
- name: Renal failure
  description: >
    Kidney failure can develop in WAGR spectrum disorder, related to WT1-associated
    nephropathy and the renal consequences of Wilms tumor and its treatment.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:34970513
    reference_title: "Results From the WAGR Syndrome Patient Registry: Characterization of WAGR Spectrum and Recommendations for Care Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients affected by WAGR syndrome can develop obesity and kidney failure"
    explanation: >
      The WAGR patient registry documents kidney failure as a recognized
      manifestation of the WAGR spectrum.
genetic:
- name: 11p13 contiguous-gene deletion
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:41818601
      reference_title: "WAGR Spectrum Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "WAGR spectrum disorder is an autosomal dominant disorder typically caused by a de novo 11p13 deletion"
      explanation: >
        GeneReviews documents the autosomal dominant inheritance with a typically de
        novo 11p13 deletion.
  features: >
    Heterozygous interstitial deletion of chromosome band 11p13 encompassing the
    contiguous WT1 and PAX6 genes, typically de novo. Deletion size is variable;
    extension distally to BDNF (11p14.1) produces the WAGRO obesity subtype.
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WAGR spectrum disorder is an autosomal dominant disorder typically caused by a de novo 11p13 deletion"
    explanation: >
      GeneReviews establishes the autosomal dominant, usually de novo, 11p13 deletion
      etiology.
  - reference: PMID:18753648
    reference_title: "Brain-derived neurotrophic factor and obesity in the WAGR syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions"
    explanation: >
      Documents the wide range of deletion sizes and the proportion extending to BDNF.
treatments:
- name: Wilms tumor surveillance
  description: >
    Routine renal imaging surveillance (e.g., abdominal/renal ultrasound on a
    scheduled interval through early childhood) is recommended for WAGR patients
    because of the high Wilms tumor risk, enabling early detection.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: MAXO:0001492
      label: surveillance for malignancies
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recommendations have been published regarding routinely scheduled follow up to monitor existing manifestations"
    explanation: >
      GeneReviews documents published scheduled surveillance recommendations, which
      include Wilms tumor monitoring given the oncologic risk.
  - reference: PMID:33146894
    reference_title: "Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised"
    explanation: >
      The SIOP-RTSG cohort advises ongoing surveillance of remaining kidney tissue
      in WAGR patients given the high rate of bilateral disease.
- name: Wilms tumor surgical resection
  description: >
    Surgical resection of Wilms tumor (nephron-sparing surgery or nephrectomy),
    the surgical component of the established multimodality Wilms tumor regimen
    that also includes chemotherapy and risk-adapted radiation, coordinated by
    pediatric oncology.
  treatment_term:
    preferred_term: nephrectomy
    term:
      id: MAXO:0001065
      label: nephrectomy
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "oncology (Wilms tumor risk assessment and management)"
    explanation: >
      GeneReviews specifies pediatric oncology management of Wilms tumor risk, which
      includes surgical resection when tumors arise.
- name: Wilms tumor chemotherapy
  description: >
    Chemotherapy is a core component of the multimodality Wilms tumor regimen in
    WAGR syndrome, given alongside surgical resection and risk-adapted radiation
    under pediatric oncology.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "oncology (Wilms tumor risk assessment and management)"
    explanation: >
      GeneReviews specifies pediatric oncology management of Wilms tumor, which
      encompasses chemotherapy as a core element of the multimodality regimen.
- name: Aniridia and ophthalmologic management
  description: >
    Multidisciplinary ophthalmologic care for complications of aniridia, including
    correction of refractive errors, tinted/photochromic lenses, glaucoma medication,
    and cautious surgical management given keratopathy and foveal hypoplasia.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301534
    reference_title: "PAX6 Aniridia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "use of topical anti-glaucoma medication to manage glaucoma when possible"
    explanation: >
      GeneReviews details ophthalmologic supportive management of aniridia
      complications such as glaucoma.
- name: Developmental and behavioral support
  description: >
    Early childhood developmental intervention and management of intellectual
    disability and neurobehavioral/psychiatric issues by developmental specialists.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early childhood development (developmental delay / intellectual disability, neurobehavioral issues)"
    explanation: >
      GeneReviews recommends developmental and neurobehavioral support as part of
      multidisciplinary WAGR care.
- name: Genetic counseling
  description: >
    Genetic counseling for recurrence-risk assessment, including parental genetic
    and chromosome evaluation for predisposing rearrangements, with prenatal and
    preimplantation genetic testing options.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:41818601
    reference_title: "WAGR Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recommended evaluations of the parents to confirm their genetic status and to allow reliable recurrence risk counseling"
    explanation: >
      GeneReviews recommends parental genetic evaluation and counseling for
      recurrence-risk assessment in WAGR spectrum disorder families.

📚

References & Deep Research

References

2

PMID:41818601

WAGR Spectrum Disorder.

No top-level findings curated for this source.

PMID:20301534

PAX6 Aniridia Syndrome.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

1. Disease Information

Edison Scientific Literature 39 citations 2026-06-03T16:15:02.515407

1. Disease Information

1.1 What is the disease?

WAGR syndrome (also framed as WAGR spectrum disorder) is a developmental and cancer predisposition syndrome due to a germline 11p13 deletion encompassing WT1 and PAX6, classically manifesting Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability/developmental delay. (hol2021clinicalcharacteristicsand pages 1-2, chbel2024conventionalandmolecular pages 1-2, duffy2021resultsfromthe pages 1-2)

Source type note: Much of the modern quantitative phenotype characterization comes from a patient registry (self-reported) (disease-level aggregation) rather than EHR-curated cohorts. (duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 29-30)

1.2 Key identifiers

OMIM: 194072 (WAGR syndrome) (chbel2024conventionalandmolecular pages 1-2)
MONDO / Orphanet / MeSH / ICD-10/ICD-11: not directly retrievable from the accessible full-text evidence in this tool run; should be populated from authoritative terminologies (Orphanet/MONDO/UMLS) in a subsequent ontology-focused lookup.

1.3 Synonyms / alternative names

WAGR syndrome (Wilms tumor–Aniridia–Genitourinary anomalies–(Range of) developmental delay) (duffy2021resultsfromthe pages 1-2)
WAGR spectrum disorder (expanded phenotypic framing) (duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 29-30)
WAGRO (WAGR + obesity; often when deletion extends to BDNF) (chbel2024conventionalandmolecular pages 1-2, duffy2021resultsfromthe pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: germline heterozygous interstitial deletion at 11p13 involving (at minimum) WT1 and PAX6. (hol2021clinicalcharacteristicsand pages 1-2, souza2022characterizationofassociated pages 1-2, chbel2024conventionalandmolecular pages 1-2)

Inheritance: Typically de novo (sporadic) but can rarely be inherited through parental chromosomal rearrangements; parental genomic/chromosome evaluation is recommended in modern reviews. (george2026wagrspectrumdisorder pages 1-3)

2.2 Risk factors

Genetic: deletion size and inclusion of additional genes may influence phenotype. For example, BDNF haploinsufficiency is linked to obesity and neurobehavioral severity within WAGR/WAGRO. (duffy2021resultsfromthe pages 1-2, han2013associationofbrainderived pages 1-2)
Environmental: No disease-specific external risk factors were identified in the retrieved WAGR-focused sources; however, for obesity/metabolic outcomes, general diet/activity factors likely modulate severity (not WAGR-specific evidence in retrieved texts).

2.3 Protective factors

No validated genetic or environmental protective factors were identified in the WAGR-focused retrieved evidence.

2.4 Gene–environment interactions

No explicit WAGR-specific GxE evidence was identified in retrieved sources.

3. Phenotypes

3.1 Core phenotypic spectrum (with frequencies where available)

Registry data (91 participants) support reframing as “WAGR spectrum” with high burden across ocular, neurodevelopmental, renal/urologic, and cardiometabolic domains. (duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 9-11)

Ocular / visual system * Eye issues: 85/85 (100%) (duffy2021resultsfromthe pages 8-9) * Nystagmus: 77/82 (93.9%) (duffy2021resultsfromthe pages 8-9) * Cataracts: 68/79 (86.1%) (duffy2021resultsfromthe pages 8-9) Suggested HPO terms: Aniridia (HP:0000526), Nystagmus (HP:0000639), Cataract (HP:0000518), Foveal hypoplasia (HP:0007750) (the last is commonly associated with aniridia but not quantified in the retrieved registry excerpts).

Wilms tumor / nephroblastomatosis predisposition * Registry: Wilms tumor and/or nephrogenic rests: 42/77 (54.5%); Wilms tumor specifically: 36/77 (46.8%) (duffy2021resultsfromthe pages 2-4) * Cohort-based risk estimate: 45%–60% lifetime Wilms tumor risk (hol2021clinicalcharacteristicsand pages 1-2) Suggested HPO terms: Wilms tumor (HP:0002667), Nephroblastomatosis / nephrogenic rests (often encoded as nephroblastomatosis; HPO usage may vary).

Neurodevelopmental / psychiatric (patient registry) * Cognitive and/or learning problems: 69/78 (88.5%) (duffy2021resultsfromthe pages 6-7) * Cognitive impairment: 45/78 (57.7%) (duffy2021resultsfromthe pages 6-7) * Global developmental delay: 44/78 (56.4%) (duffy2021resultsfromthe pages 6-7) * Autism spectrum disorder: 19/76 (25.0%) (duffy2021resultsfromthe pages 6-7) * ADD/ADHD: 18/76 (23.7%) (duffy2021resultsfromthe pages 6-7) * Anxiety disorder: 30/68 (44.1%) (duffy2021resultsfromthe pages 6-7) Suggested HPO terms: Global developmental delay (HP:0001263), Intellectual disability (HP:0001249), Autism (HP:0000717), Attention deficit hyperactivity disorder (HP:0007018), Anxiety (HP:0000739).

Neurologic / tone / seizures * Abnormal muscle control/tone: 53/77 (68.8%) (duffy2021resultsfromthe pages 8-9) * Seizures: 12/66 (18.1%) (duffy2021resultsfromthe pages 8-9) Suggested HPO terms: Hypotonia (HP:0001252), Seizures (HP:0001250).

Kidney / CAKUT / UTI / CKD * CAKUT may be underappreciated historically; “more than half” had ≥1 kidney condition (registry narrative). (duffy2021resultsfromthe pages 9-11) * CAKUT frequency in registry-derived summary: 38.5% (george2026wagrspectrumdisorder pages 3-5) * Among 15 with recurrent UTI, 9 (60.0%) had a CAKUT-consistent issue (duffy2021resultsfromthe pages 6-7) Suggested HPO terms: Congenital anomaly of kidney and urinary tract (HP:0000078), Recurrent urinary tract infections (HP:0000010), Chronic kidney disease (HP:0012622).

Cardiometabolic / obesity * Registry: “∼75% of the entire group was affected by obesity and/or hypertension” (duffy2021resultsfromthe pages 9-11) * In participants with reported BDNF deletion, ~two-thirds reported obesity (17/26) (duffy2021resultsfromthe pages 6-7) Suggested HPO terms: Obesity (HP:0001513), Hypertension (HP:0000822), Hyperlipidemia (HP:0003124), Abnormal glucose tolerance (HP:0001952).

Quality of life impact The retrieved evidence set did not include standardized QoL instruments (e.g., PROMIS, SF-36), but the high prevalence of ocular disease plus neurodevelopmental and metabolic/renal issues implies substantial lifelong functional impact and need for multidisciplinary care. (duffy2021resultsfromthe pages 9-11, george2026wagrspectrumdisorder pages 1-3)

4. Genetic / Molecular Information

4.1 Causal genes and genomic lesion

WT1 and PAX6 deletion at 11p13 is defining for WAGR; isolated PAX6 deletions are not associated with Wilms tumor, highlighting WT1 as the Wilms tumor predisposition driver. (hol2021clinicalcharacteristicsand pages 1-2)
Deletions frequently extend beyond WT1/PAX6 and may include BDNF (distal, ~4 Mb from PAX6), influencing obesity/neurobehavioral phenotypes. (han2013associationofbrainderived pages 1-2)

HGNC gene symbols: WT1, PAX6, BDNF.

4.2 Pathogenic variant class

Predominant pathogenic mechanism is copy-number loss (heterozygous deletion; contiguous gene deletion) rather than single-nucleotide variants. (hol2021clinicalcharacteristicsand pages 1-2, chbel2024conventionalandmolecular pages 2-5)

Variant type/class: structural variant / CNV (microdeletion); typically germline. (chbel2024conventionalandmolecular pages 1-2)

Allele frequency: not applicable in the conventional SNV sense; deletions are generally de novo and rare.

4.3 Modifier genes

BDNF is the best-supported modifier/extension gene for the “WAGRO” phenotype (obesity, adaptive/cognitive effects). (duffy2021resultsfromthe pages 6-7, han2013associationofbrainderived pages 1-2) A candidate-gene association study of common BDNF variants (tag SNPs) did not find strong evidence of a common-variant modifier effect on BMI in their WAGRO context, suggesting deletion/haploinsufficiency is more important than common polymorphism in driving the phenotype. (rodriguezlopez2013themodifiereffect pages 3-4)

4.4 Epigenetic information

A WAGR case study evaluated methylation at imprinting control regions and found normal methylation patterns, concluding that epigenetic contributions remain to be characterized. (takada2017sustainedendocrineprofiles pages 1-3)

4.5 Mechanistic notes (current understanding)

PAX6 haploinsufficiency disrupts ocular development → congenital aniridia and associated panocular anomalies. (rodriguezlopez2013themodifiereffect pages 3-4, chbel2024conventionalandmolecular pages 1-2)
WT1 loss disrupts kidney development/tumor suppression → high Wilms tumor risk; WAGR WT risk 45–60%. (hol2021clinicalcharacteristicsand pages 1-2, kalish2024updateonsurveillance pages 5-6)
BDNF haploinsufficiency affects hypothalamic energy-balance circuits downstream of leptin/MC4R and impacts synaptic plasticity/learning; mechanistic support comes from mouse models and human genotype–phenotype analyses. (rodriguezlopez2013themodifiereffect pages 2-3, han2013associationofbrainderived pages 1-2)

Suggested GO biological process terms (examples): * Eye development: GO:0001654 (eye development) * Kidney development: GO:0001822 (kidney development) * Regulation of feeding behavior: GO:0060259 (regulation of feeding behavior) * Synaptic plasticity: GO:0048167 (regulation of synaptic plasticity)

Suggested CL cell types (examples): * Hypothalamic neuron: CL:0000679 (neuron) (more specific hypothalamic subtypes not extractable from retrieved WAGR sources) * Podocyte relevance is discussed in WT1-related disorders broadly but not specifically extracted here.

5. Environmental Information

No WAGR-specific environmental toxin, lifestyle, or infectious triggers were identified in the retrieved disease-focused sources. Management of obesity and cardiovascular risk is nonetheless likely to involve standard lifestyle/environmental interventions as part of general care pathways (not specific to WAGR evidence in this set).

6. Mechanism / Pathophysiology

6.1 Causal chain (integrated)

1) Germline 11p13 deletion removes WT1 + PAX6 (± BDNF and other genes) → 2) Developmental dysregulation of eye structures (PAX6), genitourinary/kidney development and tumor suppression (WT1), and neurotrophic signaling impacting cognition and energy balance (BDNF) → 3) Clinical manifestations: aniridia/panocular disease, Wilms tumor predisposition, GU anomalies/CAKUT/CKD, neurodevelopmental and psychiatric disorders, obesity/metabolic syndrome features. (hol2021clinicalcharacteristicsand pages 1-2, duffy2021resultsfromthe pages 9-11, han2013associationofbrainderived pages 1-2)

6.2 BDNF haploinsufficiency as a mechanistic driver of “WAGRO” features

A key mechanistic anchor is the observation that heterozygous Bdnf knockout mice show hyperphagia/obesity and learning/social-behavior deficits, paralleling human WAGR/WAGRO features. (han2013associationofbrainderived pages 1-2)

In a WAGR cohort stratified by BDNF deletion status, BDNF+/− subjects had ~14-point lower Vineland Adaptive Behaviour scores and ~20-point lower mean IQ compared with BDNF+/+ subjects, supporting BDNF dosage as a driver of adaptive/cognitive outcomes. (han2013associationofbrainderived pages 1-2)

7. Anatomical Structures Affected

Primary organ systems * Eye (aniridia/panocular anomalies): UBERON suggestion UBERON:0000970 (eye) (duffy2021resultsfromthe pages 8-9) * Kidney (Wilms tumor risk; CAKUT; CKD): UBERON:0002113 (kidney) (hol2021clinicalcharacteristicsand pages 1-2, duffy2021resultsfromthe pages 9-11) * Genitourinary tract: UBERON:0000990 (reproductive system) and UBERON:0000057 (ureter) for CAKUT-related structures (phenotype category supported; detailed UBERON mapping not enumerated in retrieved excerpts) (chbel2024conventionalandmolecular pages 1-2) * Brain (neurodevelopmental and behavioral phenotypes): UBERON:0000955 (brain) (duffy2021resultsfromthe pages 6-7)

Subcellular/cellular components Not systematically described in retrieved WAGR-focused clinical sources.

8. Temporal Development

Onset: congenital ocular manifestations (aniridia and associated anomalies) are present early; Wilms tumor typically occurs in early childhood, with registry/case series emphasizing early surveillance. (duffy2021resultsfromthe pages 2-4, kalish2024updateonsurveillance pages 12-14)
Wilms tumor timing: SIOP-RTSG cohort median age at WT/nephroblastomatosis diagnosis 22 months (range 6–44 months). (hol2021clinicalcharacteristicsand pages 1-2)
Long-term course: CKD and cardiometabolic complications are important later morbidities; registry and guideline sources emphasize surveillance beyond childhood for kidney health. (kalish2024updateonsurveillance pages 5-6, duffy2021resultsfromthe pages 9-11)

9. Inheritance and Population

Inheritance pattern: typically autosomal dominant at the level of the deletion, but most cases are de novo. (george2026wagrspectrumdisorder pages 1-3)
Prevalence/incidence: robust population estimates were not available in the authoritative cohort/guideline sources retrieved here. Some low-authority case reports claim prevalence ranges (e.g., 1/500,000–1/1,000,000), but these were not used as a primary statistic due to limited evidentiary strength.

10. Diagnostics

10.1 Genetic testing (recommended approaches from retrieved sources)

Chromosomal microarray / array CGH (CMA): high-resolution delineation of 11p deletions and breakpoints; can detect submicroscopic deletions not seen on karyotype. (chbel2024conventionalandmolecular pages 2-5)
Conventional karyotype: can reveal complex rearrangements but may miss small deletions; still useful especially when rearrangements/translocations are suspected. (chbel2024conventionalandmolecular pages 2-5, takada2017sustainedendocrineprofiles pages 1-3)
FISH: used for targeted confirmation in some workflows; may be unnecessary if CMA clearly defines deletion; can also interrogate regulatory regions when PAX6 coding is intact. (chbel2024conventionalandmolecular pages 2-5, chbel2024conventionalandmolecular pages 1-2)
MLPA + karyotype as first-tier for newborns with aniridia in one proposed care pathway, while proceeding with tumor surveillance. (duffy2021resultsfromthe pages 14-15)
Sequencing with CNV calling / genome sequencing / exome with CNV: highlighted in contemporary WAGR spectrum review as high-resolution methods for copy-number detection and family studies. (george2026wagrspectrumdisorder pages 1-3)

10.2 Clinical surveillance tests

Wilms tumor screening: renal ultrasound-based protocols (see Treatment/Prevention sections). (kalish2024updateonsurveillance pages 12-14)

11. Outcome / Prognosis

11.1 Wilms tumor outcomes

In a 30-year SIOP-RTSG WAGR WT/nephroblastomatosis cohort (n=43): * 5-year event-free survival: 84.3% * 5-year overall survival: 91.2% with frequent nephrogenic rests (78.9%) and substantial bilateral disease (37.5%). (hol2021clinicalcharacteristicsand pages 1-2)

11.2 Long-term morbidity

Registry evidence indicates substantial long-term burden from renal disease and cardiometabolic complications; “∼75%” had obesity and/or hypertension, and kidney conditions were common. (duffy2021resultsfromthe pages 9-11)

12. Treatment

12.1 Wilms tumor

Standard Wilms tumor therapy (surgery and chemotherapy) is applied when WT develops; a WAGR endocrine case describes tumor resection and chemotherapy with favorable response. (takada2017sustainedendocrineprofiles pages 1-3)

12.2 Ophthalmologic care

WAGR management includes regular monitoring and treatment of aniridia-associated ocular complications (e.g., glaucoma, cataract, corneal changes), though detailed procedure-level recommendations were not fully enumerated in the retrieved WAGR-specific sources beyond “regular monitoring of visual function.” (chbel2024conventionalandmolecular pages 2-5, george2026wagrspectrumdisorder pages 1-3)

12.3 Neurodevelopmental / behavioral

Given high registry frequencies of learning problems, ASD/ADHD, anxiety, and tone abnormalities, early developmental services and behavioral/psychiatric care are a core component of multidisciplinary management. (duffy2021resultsfromthe pages 6-7, george2026wagrspectrumdisorder pages 1-3)

12.4 Obesity and cardiometabolic risk

Registry data demonstrate frequent obesity/hypertension, especially among those with BDNF deletion, supporting early monitoring of weight trajectory, blood pressure, lipids, and glucose, integrated with standard pediatric obesity interventions. (duffy2021resultsfromthe pages 9-11, duffy2021resultsfromthe pages 6-7, george2026wagrspectrumdisorder pages 13-16)

12.5 Multidisciplinary care model (expert synthesis)

Registry authors explicitly conclude that “A comprehensive care management approach is needed … and we propose a care model” for WAGR spectrum disorder, emphasizing coordinated longitudinal care. (duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 29-30)

MAXO term suggestions (examples): * Renal ultrasound surveillance: MAXO:0000837 (ultrasonography) (ontology mapping suggestion) * Genetic counseling: MAXO:0000079 (genetic counseling) * Multidisciplinary care coordination: MAXO:0000138 (care coordination)

13. Prevention

Primary prevention: not generally applicable (germline deletion typically de novo), but reproductive counseling and prenatal/preimplantation options may be offered once a familial rearrangement/deletion is identified. (george2026wagrspectrumdisorder pages 13-16)

Secondary prevention (early detection): Wilms tumor surveillance * AACR 2024 guidance: ultrasound surveillance every 3 months until the 7th birthday for WT predisposition syndromes (renal ultrasound when only WT risk; complete abdominal US if hepatoblastoma risk also applies). (kalish2024updateonsurveillance pages 12-14) * WAGR registry care recommendation: renal ultrasound every 3 months below age 8 years, then individualized; at least annual renal ultrasound recommended for long-term kidney health monitoring. (duffy2021resultsfromthe pages 18-19)

Tertiary prevention: monitoring/management of CKD progression and cardiometabolic risk factors to reduce long-term morbidity. (duffy2021resultsfromthe pages 9-11, george2026wagrspectrumdisorder pages 13-16)

14. Other Species / Natural Disease

No naturally occurring veterinary analogue of WAGR syndrome was identified in the retrieved sources.

15. Model Organisms

BDNF-related WAGR/WAGRO features are supported by animal models referenced in WAGR-focused human studies: heterozygous Bdnf knockout mice show hyperphagia/obesity and learning/social-behavior deficits, aligning with obesity and neurodevelopmental phenotypes in BDNF-deleted WAGR individuals. (han2013associationofbrainderived pages 1-2)

Recent developments and real-world implementation highlights (2023–2024 emphasis)

1) Updated cancer surveillance guidance (2024): AACR Pediatric Cancer Working Group updated recommendations; WAGR is categorized as high-risk for WT (45–60%) and therefore fits standardized q3-month ultrasound surveillance through early childhood. (kalish2024updateonsurveillance pages 5-6, kalish2024updateonsurveillance pages 12-14)

2) Cytogenetic diagnostic implementation (2024 case report): Practical workflows using karyotype + array CGH (with FISH as needed) to define deletion size/breakpoints and guide surveillance and counseling, emphasizing the importance of differentiating isolated aniridia from WAGR. (chbel2024conventionalandmolecular pages 2-5, chbel2024conventionalandmolecular pages 1-2)

3) Registry-driven care models: WAGR patient registry data are being used to formalize multidisciplinary care pathways and quantify the expanded phenotype (renal, metabolic, neuropsychiatric), which supports real-world implementation of coordinated long-term surveillance beyond Wilms tumor screening. (duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 9-11)

Evidence tables and figures

The following table consolidates key identifiers, genes, quantitative risks/frequencies, and surveillance recommendations.

Item	Value/Recommendation	Evidence type (guideline/cohort/registry/case report)	Source (citation id)
Disease name	WAGR syndrome; increasingly reframed as WAGR spectrum disorder because manifestations extend beyond the classic acronym	Registry synthesis / review	(duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 29-30)
OMIM identifier	OMIM #194072	Case series / review	(chbel2024conventionalandmolecular pages 1-2)
Common expansion of acronym	Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays; older literature may use “mental retardation/intellectual disability”	Registry / review	(duffy2021resultsfromthe pages 1-2, chbel2024conventionalandmolecular pages 1-2)
Synonym / subtype term	WAGRO used when childhood-onset obesity is present, typically with deletion extending to BDNF	Case report / registry	(chbel2024conventionalandmolecular pages 1-2, duffy2021resultsfromthe pages 1-2)
Core genomic lesion	Contiguous 11p13 deletion involving WT1 and PAX6 is the defining lesion for WAGR syndrome	Cohort / review / case report	(hol2021clinicalcharacteristicsand pages 1-2, chbel2024conventionalandmolecular pages 1-2, souza2022characterizationofassociated pages 1-2)
Core genes	WT1 (tumor suppressor, kidney/gonadal development) and PAX6 (ocular/neurodevelopment)	Cohort / review / case report	(hol2021clinicalcharacteristicsand pages 1-2, chbel2024conventionalandmolecular pages 1-2, souza2022characterizationofassociated pages 1-2)
Modifier / extension gene	BDNF deletion occurs in about ~50% of registry respondents with molecular data and is associated with obesity; WAGRO concept reflects this extension	Registry	(duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 2-4)
Other candidate genes in expanded phenotype	Additional genes in larger deletions may contribute to behavioral/cognitive or nonclassic phenotypes (e.g., PRRG4 and others discussed in region-based studies)	Review / genotype-phenotype study	(george2026wagrspectrumdisorder pages 18-20, souza2022characterizationofassociated pages 15-15)
Lifetime Wilms tumor risk in WAGR	45%–60%	Guideline / cohort	(kalish2024updateonsurveillance pages 5-6, hol2021clinicalcharacteristicsand pages 1-2)
Registry frequency of Wilms tumor / nephrogenic rests	42/77 (54.5%) reported Wilms tumor and/or nephrogenic rests	Registry	(duffy2021resultsfromthe pages 2-4)
Registry frequency of Wilms tumor specifically	36/77 (46.8%) developed Wilms tumor	Registry	(duffy2021resultsfromthe pages 2-4)
Age at WT/nephroblastomatosis diagnosis	Median 22 months (range 6–44 months) in SIOP-RTSG series	Cohort	(hol2021clinicalcharacteristicsand pages 1-2)
Bilateral WT frequency	37.5% bilateral disease in SIOP-RTSG cohort	Cohort	(hol2021clinicalcharacteristicsand pages 1-2)
Metastatic / anaplastic WT in cohort	No metastases or anaplasia reported in the SIOP-RTSG cohort; nephrogenic rests were common (78.9%)	Cohort	(hol2021clinicalcharacteristicsand pages 1-2)
WT outcomes	5-year event-free survival 84.3%; overall survival 91.2%	Cohort	(hol2021clinicalcharacteristicsand pages 1-2)
BDNF deletion frequency	Registry molecular-response subset: 27/54 (~50%) selected BDNF deletion	Registry	(duffy2021resultsfromthe pages 2-4)
Obesity among those with reported BDNF deletion	17/26 (~65%) reported obesity; 7/22 (~32%) reported obesity with short stature	Registry	(duffy2021resultsfromthe pages 6-7)
Cardiometabolic burden	~75% of the WAGR Discovery Cohort had obesity and/or hypertension	Registry	(duffy2021resultsfromthe pages 9-11)
Kidney involvement	More than half of participants had at least one kidney condition; CAKUT may be underappreciated in WAGR	Registry	(duffy2021resultsfromthe pages 9-11)
CAKUT frequency	38.5% reported in registry-derived summary	Registry synthesis	(george2026wagrspectrumdisorder pages 3-5)
Recurrent UTI association	Among 15 with recurrent UTIs, 9 (60.0%) had a CAKUT-consistent issue	Registry	(duffy2021resultsfromthe pages 6-7)
Cognitive/learning problems	69/78 (88.5%)	Registry	(duffy2021resultsfromthe pages 6-7)
Cognitive impairment	45/78 (57.7%)	Registry	(duffy2021resultsfromthe pages 6-7)
Global developmental delay	44/78 (56.4%)	Registry	(duffy2021resultsfromthe pages 6-7)
Autism spectrum disorder	19/76 (25.0%)	Registry	(duffy2021resultsfromthe pages 6-7)
ADD/ADHD	18/76 (23.7%)	Registry	(duffy2021resultsfromthe pages 6-7)
Anxiety disorder	30/68 (44.1%)	Registry	(duffy2021resultsfromthe pages 6-7)
Neurologic / muscle tone abnormalities	Abnormal muscle control/tone 53/77 (68.8%); seizures 12/66 (18.1%); neurological problems 28/74 (37.8%)	Registry	(duffy2021resultsfromthe pages 8-9)
Ocular involvement	Eye issues were universal in registry participants with available data (85/85, 100%); aniridia was nearly universal	Registry	(duffy2021resultsfromthe pages 8-9, duffy2021resultsfromthe pages 2-4)
AACR 2024 WT surveillance principle	WAGR WT risk is high and surveillance follows standard WT predisposition recommendations	Guideline	(kalish2024updateonsurveillance pages 5-6, kalish2024updateonsurveillance pages 12-14)
AACR 2024 WT surveillance modality and interval	Renal ultrasound every 3 months until the 7th birthday for WT-predisposition syndromes without hepatoblastoma risk	Guideline	(kalish2024updateonsurveillance pages 12-14)
Rationale for AACR age cutoff	Surveillance window chosen to cover the age range in which ~95% of WT develop	Guideline	(kalish2024updateonsurveillance pages 12-14)
Registry care recommendation for WT surveillance	Renal ultrasound every 3 months below age 8 years for all patients considered at risk; more frequent if abnormalities suspected	Registry care recommendation	(duffy2021resultsfromthe pages 18-19)
Registry long-term renal follow-up	After age 8, renal ultrasound frequency should be individualized; at least annual renal ultrasound recommended to monitor CKD risk	Registry care recommendation	(duffy2021resultsfromthe pages 18-19)
Additional renal concern	Because WAGR carries significant CKD risk, kidney-health monitoring should continue into adolescence and beyond	Guideline / registry care recommendation	(kalish2024updateonsurveillance pages 5-6, duffy2021resultsfromthe pages 18-19)

Table: This table consolidates identifiers, genomic basis, quantitative clinical risks, phenotype frequencies, and current Wilms tumor surveillance recommendations for WAGR syndrome/WAGR spectrum disorder. It is useful as a compact evidence map for populating disease knowledge-base fields with cited values.

A registry figure supporting cardiometabolic features in CKD-affected participants was retrieved and is available for visual reference. (duffy2021resultsfromthe media 332392c7)

Key limitations of this evidence set

Ontology identifiers (MONDO/Orphanet/MeSH/ICD): not extracted from the retrieved full-text corpus in this run; these should be added from authoritative terminologies.
Epidemiology: robust population-based prevalence/incidence estimates were not available from high-authority epidemiologic studies in the retrieved evidence; registry and clinical cohorts are not designed to estimate population prevalence.
2023–2024 mechanistic breakthroughs: the most direct mechanistic genotype–phenotype evidence for BDNF in WAGR remains anchored in 2011–2017 era primary studies, while 2024 contributions in the retrieved set are strongest in surveillance and diagnostics.

URLs and publication dates (from retrieved primary sources)

Kalish JM et al. Clinical Cancer Research. Sep 2024. “Update on surveillance for Wilms tumor and hepatoblastoma…” https://doi.org/10.1158/1078-0432.ccr-24-2100 (kalish2024updateonsurveillance pages 5-6, kalish2024updateonsurveillance pages 12-14)
Chbel F et al. Egyptian Journal of Medical Human Genetics. Mar 2024. “Conventional and molecular cytogenetic characterization…” https://doi.org/10.1186/s43042-024-00514-5 (chbel2024conventionalandmolecular pages 2-5)
Duffy KA et al. Frontiers in Pediatrics. Dec 2021. “Results From the WAGR Syndrome Patient Registry…” https://doi.org/10.3389/fped.2021.733018 (duffy2021resultsfromthe pages 1-2, duffy2021resultsfromthe pages 2-4)
Hol JA et al. Cancer. Nov 2021. “30-year SIOP-RTSG experience…” https://doi.org/10.1002/cncr.33304 (hol2021clinicalcharacteristicsand pages 1-2)
Han JC et al. Cortex. Nov 2013. “BDNF haploinsufficiency… adaptive behaviour…” https://doi.org/10.1016/j.cortex.2013.02.009 (han2013associationofbrainderived pages 1-2)
Rodríguez-López R et al. Gene. Mar 2013. “Modifier effect of the BDNF gene…” https://doi.org/10.1016/j.gene.2012.11.073 (rodriguezlopez2013themodifiereffect pages 1-2)
Takada Y et al. BMC Medical Genetics. Oct 2017. “Sustained endocrine profiles…” https://doi.org/10.1186/s12881-017-0477-5 (takada2017sustainedendocrineprofiles pages 1-3)

References

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(george2026wagrspectrumdisorder pages 1-3): AM George, Z Katz, and ER Hathaway. Wagr spectrum disorder. Unknown journal, 2026.
(han2013associationofbrainderived pages 1-2): Joan C. Han, Audrey Thurm, Christine Golden Williams, Lisa A. Joseph, Wadih M. Zein, Brian P. Brooks, John A. Butman, Sheila M. Brady, Shannon R. Fuhr, Melanie D. Hicks, Amanda E. Huey, Alyson E. Hanish, Kristen M. Danley, Margarita J. Raygada, Owen M. Rennert, Keri Martinowich, Stephen J. Sharp, Jack W. Tsao, and Susan E. Swedo. Association of brain-derived neurotrophic factor (bdnf) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in wagr/11p13 deletion syndrome. Cortex, 49(10):2700-2710, Nov 2013. URL: https://doi.org/10.1016/j.cortex.2013.02.009, doi:10.1016/j.cortex.2013.02.009. This article has 86 citations and is from a domain leading peer-reviewed journal.
(duffy2021resultsfromthe pages 2-4): Kelly A. Duffy, Kelly L. Trout, Jennifer M. Gunckle, Shari McCullen Krantz, John Morris, and Jennifer M. Kalish. Results from the wagr syndrome patient registry: characterization of wagr spectrum and recommendations for care management. Frontiers in Pediatrics, Dec 2021. URL: https://doi.org/10.3389/fped.2021.733018, doi:10.3389/fped.2021.733018. This article has 42 citations.
(duffy2021resultsfromthe pages 6-7): Kelly A. Duffy, Kelly L. Trout, Jennifer M. Gunckle, Shari McCullen Krantz, John Morris, and Jennifer M. Kalish. Results from the wagr syndrome patient registry: characterization of wagr spectrum and recommendations for care management. Frontiers in Pediatrics, Dec 2021. URL: https://doi.org/10.3389/fped.2021.733018, doi:10.3389/fped.2021.733018. This article has 42 citations.
(george2026wagrspectrumdisorder pages 3-5): AM George, Z Katz, and ER Hathaway. Wagr spectrum disorder. Unknown journal, 2026.
(chbel2024conventionalandmolecular pages 2-5): Faiza Chbel, Hasna Hamdaoui, Houssein Mossafa, Karim Ouldim, and Houda Benrahma. Conventional and molecular cytogenetic characterization of a moroccan patient with wagr syndrome. Egyptian Journal of Medical Human Genetics, Mar 2024. URL: https://doi.org/10.1186/s43042-024-00514-5, doi:10.1186/s43042-024-00514-5. This article has 2 citations and is from a peer-reviewed journal.
(rodriguezlopez2013themodifiereffect pages 3-4): Raquel Rodríguez-López, José M. Carbonell Pérez, Aránzazu Margallo Balsera, Guillermo Gervasini Rodríguez, Trinidad Herrera Moreno, Mayte García de Cáceres, Marta González-Carpio Serrano, Felipe Casanueva Freijo, Juan Ramón González Ruiz, Francisco Barros Angueira, Pilar Méndez Pérez, Manuela Núñez Estévez, and Enrique Galán Gómez. The modifier effect of the bdnf gene in the phenotype of the wagro syndrome. Gene, 516 2:285-90, Mar 2013. URL: https://doi.org/10.1016/j.gene.2012.11.073, doi:10.1016/j.gene.2012.11.073. This article has 35 citations and is from a peer-reviewed journal.
(takada2017sustainedendocrineprofiles pages 1-3): Yui Takada, Yasunari Sakai, Yuki Matsushita, Kazuhiro Ohkubo, Yuhki Koga, Satoshi Akamine, Michiko Torio, Yoshito Ishizaki, Masafumi Sanefuji, Hiroyuki Torisu, Chad A. Shaw, Masayo Kagami, Toshiro Hara, and Shouichi Ohga. Sustained endocrine profiles of a girl with wagr syndrome. BMC Medical Genetics, Oct 2017. URL: https://doi.org/10.1186/s12881-017-0477-5, doi:10.1186/s12881-017-0477-5. This article has 8 citations and is from a peer-reviewed journal.
(rodriguezlopez2013themodifiereffect pages 2-3): Raquel Rodríguez-López, José M. Carbonell Pérez, Aránzazu Margallo Balsera, Guillermo Gervasini Rodríguez, Trinidad Herrera Moreno, Mayte García de Cáceres, Marta González-Carpio Serrano, Felipe Casanueva Freijo, Juan Ramón González Ruiz, Francisco Barros Angueira, Pilar Méndez Pérez, Manuela Núñez Estévez, and Enrique Galán Gómez. The modifier effect of the bdnf gene in the phenotype of the wagro syndrome. Gene, 516 2:285-90, Mar 2013. URL: https://doi.org/10.1016/j.gene.2012.11.073, doi:10.1016/j.gene.2012.11.073. This article has 35 citations and is from a peer-reviewed journal.
(duffy2021resultsfromthe pages 14-15): Kelly A. Duffy, Kelly L. Trout, Jennifer M. Gunckle, Shari McCullen Krantz, John Morris, and Jennifer M. Kalish. Results from the wagr syndrome patient registry: characterization of wagr spectrum and recommendations for care management. Frontiers in Pediatrics, Dec 2021. URL: https://doi.org/10.3389/fped.2021.733018, doi:10.3389/fped.2021.733018. This article has 42 citations.
(george2026wagrspectrumdisorder pages 13-16): AM George, Z Katz, and ER Hathaway. Wagr spectrum disorder. Unknown journal, 2026.
(duffy2021resultsfromthe pages 18-19): Kelly A. Duffy, Kelly L. Trout, Jennifer M. Gunckle, Shari McCullen Krantz, John Morris, and Jennifer M. Kalish. Results from the wagr syndrome patient registry: characterization of wagr spectrum and recommendations for care management. Frontiers in Pediatrics, Dec 2021. URL: https://doi.org/10.3389/fped.2021.733018, doi:10.3389/fped.2021.733018. This article has 42 citations.
(george2026wagrspectrumdisorder pages 18-20): AM George, Z Katz, and ER Hathaway. Wagr spectrum disorder. Unknown journal, 2026.
(souza2022characterizationofassociated pages 15-15): Vanessa Sodré de Souza, Gabriela Corassa Rodrigues da Cunha, Beatriz R. Versiani, Claudiner Pereira de Oliveira, Maria Teresa Alves Silva Rosa, Silviene F. de Oliveira, Patricia N. Moretti, Juliana F. Mazzeu, and Aline Pic-Taylor. Characterization of associated nonclassical phenotypes in patients with deletion in the wagr region identified by chromosomal microarray: new insights and literature review. Molecular Syndromology, 13:1-15, Feb 2022. URL: https://doi.org/10.1159/000518872, doi:10.1159/000518872. This article has 2 citations and is from a peer-reviewed journal.
(duffy2021resultsfromthe media 332392c7): Kelly A. Duffy, Kelly L. Trout, Jennifer M. Gunckle, Shari McCullen Krantz, John Morris, and Jennifer M. Kalish. Results from the wagr syndrome patient registry: characterization of wagr spectrum and recommendations for care management. Frontiers in Pediatrics, Dec 2021. URL: https://doi.org/10.3389/fped.2021.733018, doi:10.3389/fped.2021.733018. This article has 42 citations.
(rodriguezlopez2013themodifiereffect pages 1-2): Raquel Rodríguez-López, José M. Carbonell Pérez, Aránzazu Margallo Balsera, Guillermo Gervasini Rodríguez, Trinidad Herrera Moreno, Mayte García de Cáceres, Marta González-Carpio Serrano, Felipe Casanueva Freijo, Juan Ramón González Ruiz, Francisco Barros Angueira, Pilar Méndez Pérez, Manuela Núñez Estévez, and Enrique Galán Gómez. The modifier effect of the bdnf gene in the phenotype of the wagro syndrome. Gene, 516 2:285-90, Mar 2013. URL: https://doi.org/10.1016/j.gene.2012.11.073, doi:10.1016/j.gene.2012.11.073. This article has 35 citations and is from a peer-reviewed journal.

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Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 What is the disease?

1.2 Key identifiers

1.3 Synonyms / alternative names

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotypic spectrum (with frequencies where available)

4. Genetic / Molecular Information

4.1 Causal genes and genomic lesion

4.2 Pathogenic variant class

4.3 Modifier genes

4.4 Epigenetic information

4.5 Mechanistic notes (current understanding)

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Causal chain (integrated)

6.2 BDNF haploinsufficiency as a mechanistic driver of “WAGRO” features

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

10.1 Genetic testing (recommended approaches from retrieved sources)

10.2 Clinical surveillance tests

11. Outcome / Prognosis

11.1 Wilms tumor outcomes

11.2 Long-term morbidity

12. Treatment

12.1 Wilms tumor

12.2 Ophthalmologic care

12.3 Neurodevelopmental / behavioral

12.4 Obesity and cardiometabolic risk

12.5 Multidisciplinary care model (expert synthesis)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Recent developments and real-world implementation highlights (2023–2024 emphasis)

Evidence tables and figures

Key limitations of this evidence set

URLs and publication dates (from retrieved primary sources)

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