• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The WT1 gene is associated with autosomal dominant Denys-Drash syndrome (MedGen UID: 181980), Wilms tumor (MedGen UID: 447509), WAGR syndrome (MedGen UID: 64512), and Frasier syndrome (MedGen UID: 215533).

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The WT1 gene encodes a transcription factor, which plays a role in normal development of the urogenital system and mesothelial tissues.

OMIM: 607102

Clinical condition
The WT1 gene is associated with both isolated Wilms tumor (MedGen UID: 447509) and syndromic Wilms tumor, including autosomal dominant Denys-Drash syndrome (DDS; MedGen UID: 181980), WAGR syndrome (Wilms tumor, aniridia, genital abnormalities, mental retardation; MedGen UID: 64512), and Frasier syndrome (FS; MedGen UID: 215533).

Wilms tumor (nephroblastoma) is an embryonal renal cancer that occurs almost exclusively in children and is the most common childhood renal malignancy, affecting 1 in 10,000 children (PMID: 28716159). Pathogenic germline variants in WT1 are responsible for 5% of isolated Wilms tumor cases (PMID: 28716159).

WAGR syndrome is caused by a deletion on chromosome 11 inclusive of both the WT1 and the PAX6genes. It is associated with aniridia (absence of color in the iris), abnormalities of the genitals or urinary tract, and intellectual disability (PMID: 14114111, 208044). In individuals with WAGR syndrome, the risk of Wilms tumor is 45-57%. Tumors present earlier, are more often bilateral, and more often lead to the development of end-stage renal disease than in isolated Wilms tumor cases (PMID: 17630404, 14673045, 11920832). Aniridia is typically the first noticeable sign of WAGR syndrome. Intellectual disability as well as psychiatric and behavioral problems are also common (PMID: 16199712). The most common genitourinary anomaly in males is cryptorchidism, while females may have underdeveloped ovarian tissue and bicornuate uterus (PMID: 16199712).

DDS is characterized by abnormal urogenital development resulting in renal failure and disorders of sexual development (DSD) with increased risk for Wilms tumor (PMID: 1655284). Renal disease, specifically diffuse glomerulosclerosis, usually begins within the first year of life and quickly leads to kidney failure (PMID: 1655284). Affected males can have ambiguous to normal female genitalia, while affected females usually have typical sexual development and are sometimes diagnosed with isolated nephrotic syndrome (PMID: 1655284). Because affected females typically have normal genitalia and gonads and only manifest the renal features, they are often diagnosed with isolated nephrotic syndrome (PMID: 22763603). The risk for Wilms tumor is high (greater than 90%) with a potentially early onset (9-18 months; PMID: 15150775, 8071974).

FS is characterized by abnormal urogenital development leading to end-stage renal disease, DSD, and risk for gonadal and Wilms tumor (PMID: 25623218). Childhood-onset nephrotic syndrome, specifically focal segmental glomerulosclerosis, progresses to kidney failure in adolescence (PMID: 25623218). Most affected individuals have external female genitalia regardless of karyotype, although affected males may have male or ambiguous external genitalia, and internal gonads may require surgical removal due to risk of gonadoblastoma (PMID: 25623218). Affected females are often diagnosed with isolated nephrotic syndrome because they typically have normal genitalia and gonads and only manifest the renal features (PMID: 22763603). Wilms tumor has been reported, but it is not a primary feature (PMID: 15357247). Due to the significant clinical overlap, it is suspected that FS and DDS may be variable clinical presentations of the same condition (PMID: 22763603).

Gene information
The WT1 gene encodes a protein transcription factor that represses, and occasionally activates, the expression of downstream target genes guiding the development of the urogenital system and mesothelial tissues (PMID: 2163761, 1572653).

Loss-of-function variants in WT1 are known to be pathogenic. In a study of 117 patients with WT1mutations, several genotype-phenotype correlations were detected (PMID:15150775):

  • Truncating mutations lead to an earlier age of onset (~12.5 months) and a high number of bilateral tumors and genital tract anomalies (in 52% of cases).
  • Missense mutations lead to a somewhat later age of onset (~18 months).
  • Deletions lead to the latest age of onset (~22 months).
    The most common WT1 pathogenic changes in DDS are in exons 8 and 9 (PMID: 28068926), while WT1 pathogenic variants in the donor splice site at intron 9 cause FS (PMID: 28068926).

WT1 variants are inherited in an autosomal dominant manner. This means that an individual with a pathogenic variant has a 50% chance of passing the variant on to their offspring. While a few cases are inherited, most cases occur as the result of a spontaneous de novo variant (PMID: 9781905). Identification of a pathogenic variant in an affected individual guides testing and diagnosis of at-risk relatives.

Pathogenic variants in WT1 exhibit decreased penetrance and variable expression (PMID: 9781905), meaning that the finding of a pathogenic variant in WT1 is not a diagnosis of cancer, and that not all individuals with a genetic change in WT1 will develop cancer or have all of the associated conditions.

There are no established screening or surveillance guidelines for individuals with a pathogenic WT1variant, but management recommendations have recently been proposed. There is an updated consensus statement for the care of individuals with DSD (PMID: 26820577).

  • Individuals at risk for Wilms tumor should be followed by a clinical geneticist or pediatric oncologist twice yearly for a physical exam, and should have renal ultrasounds every 3 months until the age of 7 years (PMID: 28674120).
  • Surgical and chemotherapy interventions have improved the prognosis for patients with Wilms tumor (PMID: 28516188, 18816692).
  • Evaluation for gonadal dysgenesis in 46,XY individuals should include hormone assessment and imaging (PMID: 21508141, 28674120).
  • Patients with WT1 pathogenic variants also need to be followed closely for nephropathy and gonadal tumors, with an early gonadectomy recommended in FS (PMID: 21508141).
  • Patients with WT1-related DSD benefit from treatment by a multidisciplinary DSD clinic (PMID: 26820577).

Review date: January 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
WT1 NM_024426.4