This test analyzes the WT1 gene, which is associated with isolated Wilms tumor and with syndromic causes of Wilms tumor, including WAGR (Wilms, aniridia, genitourinary, retardation), Denys-Drash syndrome (DDS), and Frasier syndrome.
Genetic testing of WT1 may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
Rarely, cases of Wilms tumor are due to a contiguous gene deletion that encompasses both the PAX6 and WT1 genes and that causes Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome. In the presence of any of aniridia, the WAGR syndrome test, which includes the PAX6 gene, may be more appropriate.
(Nephroblastoma) is an embryonal renal cancer that is made up of some combination of blastemal, epithelial, and stromal cells and is the most common renal malignancy in childhood. Hereditary pathogenic variants in WT1 explain approximately 5% of Wilms tumor cases. Such variants can cause non-syndromic isolated Wilms tumor as well as syndromes of which Wilms is a feature—particularly WAGR (Wilms, aniridia, genitourinary, retardation), Denys-Drash (DDS), and Frasier syndromes.
WAGR syndrome is caused by a deletion on chromosome 11 inclusive of both WT1 and the PAX6 gene, which is associated with aniridia (absence of color in the iris). Aniridia is typically the first noticeable sign of WAGR syndrome. In individuals with WAGR syndrome, Wilms tumor presents earlier and is more often bilateral than in isolated Wilms tumor cases. Intellectual disability is common, as are psychiatric or behavioral problems. The most common genitourinary anomalies in males is cryptorchidism. Females may have underdeveloped ovarian tissue and bicornuate uterus, leading to fertility issues.
Denys-Drash syndrome (DDS)
DDS is a condition that affects the kidneys and genitalia. Renal disease, specifically diffuse glomerulosclerosis, begins within the first year of life and often leads to kidney failure. The risk for Wilms tumor is greater than 90%. Affected males have ambiguous genitalia due to gonadal dysgenesis and may be infertile. Because affected females typically have normal genitalia and only manifest the renal features of DDS, they are often diagnosed with isolated nephrotic syndrome.
Frasier syndrome is similar to DDS, affects the kidneys and genitalia. Childhood-onset renal disease—specifically focal segmental glomerulosclerosis—often leads to kidney failure in adolescence. Affected males have ambiguous genitalia and underdeveloped internal gonads that may require surgical removal due to risks of gonadoblastoma. Because affected females typically have normal genitalia and gonads and only manifest the renal features, they are often diagnosed with isolated nephrotic syndrome. Wilms tumor has been reported in some cases, but it is not a primary feature. Due to the significant clinical overlap with DDS, it is suspected that Frasier and DDS may be variable clinical presentations of the same condition.
In addition to the syndromes above, some individuals with pathogenic variants in WT1 may present with genitourinary anomalies and Wilms tumor in the absence of renal failure.
|Condition||Wilms tumor||Gonadoblastoma||References (PMIDs)|
|Non-syndromic WT1 pathogenic variants||Elevated||-||12193442, 25688735|
|WAGR syndrome||40%–50%||-||11479730, 11920832|
|Denys-Drash syndrome||Estimated 90%||40%||15150775, 8827067, 25623218, 20301471|
Elevated: There is evidence of association, but penetrance or risk is not well characterized.
WT1-related disorders are inherited in an autosomal dominant manner. Though a few cases are inherited, most occur as the result of a spontaneous de novo pathogenic variant.
Analysis of the WT1 gene may be considered in individuals with a personal and/or family history of:
For management resources, please refer to:
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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|