Table 1.

More Common Genes, Loci, and Syndromes Associated with Wilms Tumor Predisposition

Gene / LocusSyndrome% of all Wilms tumorMOIEstimated Wilms Tumor RiskOther Features
REST REST-related Wilms tumor (OMIM 616806)~2%ADUnknown
TRIM28 TRIM28-related Wilms tumor 1~2%ADUnknownEvidence of maternal parent-of-origin effect
WT1 WT1 disorder 1%-5%ADVaries by genotype:
  • Highest risk: truncating variants
  • 70%-80%: exon 8/9 missense variants
  • <2%: intron 9 variants
  • Other variants have intermediate risk. 1
GU anomalies more common in males 2, undermasculinized genitalia, renal mesangial sclerosis, steroid resistant nephrotic syndrome, gonadoblastoma 3
11p13WAGR syndrome (See PAX6-Related Aniridia.)0%-1%AD45%-60%Aniridia, GU anomalies, ambiguous genitalia, gonadoblastoma, ID, ESRD, obesity
11p15 411p15-related Wilms tumor, incl isolated Wilms tumor 4, Beckwith-Wiedemann syndrome (BWS), and isolated hemi-hyperplasia 5 (OMIM 235000)1%-5%See footnote 6.~7%-25%In BWS: macrosomia, macroglossia, hemihyperplasia, visceromegaly, embryonal tumors (e.g., hepatoblastoma, neuroblastoma, rhabdomyosarcoma, adrenal cortical carcinoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, & renal abnormalities

AD = autosomal dominant; ESRD = end-stage renal disease; GU = genitourinary; ID = intellectual disability; MOI = mode of inheritance

1.
2.

Germline WT1 pathogenic variants have a greater effect on sex determination and genital tract development in males; 46,XX females with a germline WT1 pathogenic variant are less likely to exhibit genitourinary anomalies.

3.

In the absence of genitourinary anomalies, renal mesangial sclerosis, nephrogenic rests, or bilateral tumors, the likelihood that a child with Wilms tumor has a germline WT1 pathogenic variant is 0%-5%. A small number of families with isolated Wilms tumor have heterozygous germline WT1 pathogenic variants.

4.

Isolated Wilms tumor has been associated with constitutional alterations of chromosome 11p15 most commonly hypermethylation at IC1 and paternal uniparental disomy of 11p15. Loss of methylation at IC2 and genomic abnormalities of 11p15 may be associated with Wilms tumor but reports are rare and the evidence is still emerging.

5.

Molecular alterations at 11p15 including loss of methylation at IC2, gain of methylation at IC1, and 11p15 paternal uniparental disomy have been reported in individuals who have apparently isolated hemihyperplasia (see Beckwith-Wiedemann Syndrome, Allelic Disorders).

6.

85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission.

From: Wilms Tumor Predisposition

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