The Invitae Wilms Tumor Panel analyzes genes associated with both isolated and syndromic causes of Wilms tumor including WAGR (Wilms, aniridia, genitourinary, retardation), Denys-Drash syndrome (DDS), Beckwith-Wiedemann syndrome, Frasier syndrome, Simpson-Golabi-Behmel syndrome, Perlman syndrome and CDC73-related conditions.
The primary panel includes 6 genes associated with Wilms tumor. In addition to the primary panel, clinicians can also choose to include the CTR9 gene, which has preliminary evidence of an association with this cancer type. At this time, the association of this gene with Wilms tumor remains uncertain; however, some clinicians may wish to include genes that may prove to be clinically significant in the future. This gene can be added at no additional charge.
Genetic testing of these genes 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.
CDC73 CDKN1C DIS3L2 GPC3 REST WT1
CTR9
Genes with preliminary evidence of association with Wilms tumor are available to add on to the primary panel. Adding on preliminary-evidence genes can increase the number of variants of uncertain significance that are identified. Some clinicians may wish to include genes that do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. Visit our Preliminary-evidence genes page to learn more.
CDC73 CDKN1C DIS3L2 GPC3 REST WT1
Genes with preliminary evidence of association with Wilms tumor are available to add on to the primary panel. Adding on preliminary-evidence genes can increase the number of variants of uncertain significance that are identified. Some clinicians may wish to include genes that do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. Visit our Preliminary-evidence genes page to learn more.
CTR9
These genes can also be ordered as part of a broader panel to test for hereditary causes of renal/urinary tract cancer. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional charge.
Wilms tumor (nephroblastoma) is an embryonal renal cancer comprised of a combination of blastemal, epithelial and stromal cells and is the most common renal malignancy in childhood. Several genes are associated with Wilms tumor, including CDKN1C, DIS3L2, GPC3, CDC73 and WT1. Variants in these genes can cause nonsyndromic isolated Wilms tumor as well as syndromes of which Wilms is a feature. These conditions include the following:
Beckwith-Wiedemann syndrome
This is an overgrowth condition with features including hemihyperplasia, omphalocele, umbilical hernia, macroglossia, visceromegaly, creases or pits in the skin near the ears, and neonatal hypoglycemia. Affected individuals have an increased risk of developing multiple benign and malignant tumors—particularly Wilms tumor, hepatoblastoma and rhabdomyosarcoma. This panel assesses for pathogenic variants in the CDKN1C gene, which account for 40% of familial cases of Beckwith-Wiedemann syndrome and 5% of cases with no reported family history of the condition.
Simpson-Golabi-Behmel syndrome type 1 (SGBS1)
SGBS1 is a rare, X-linked overgrowth disorder that is the result of pathogenic variants in the GPC3 gene. This condition presents in the prenatal or neonatal period. Affected males typically have intellectual disability, macrosomia, cardiac, skeletal, gastrointestinal and genitourinary anomalies, hepatosplenomegaly, and distinctive facial features that include macrocephaly, macrostomia (large, wide mouth) and macroglossia (enlarged tongue). There is an increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma and hepatocellular carcinoma.
Perlman syndrome
Perlman syndrome is a rare overgrowth condition that is the result of pathogenic variants in the DIS3L2 gene. This disorder is characterized by fetal/neonatal macrosomia, polyhydramnios, nephromegaly, distinctive facial features, developmental delay, renal dysplasia, nephroblastomatosis and predisposition to Wilms tumor. The prognosis of Perlman syndrome is poor, with a high neonatal mortality rate. Among infants who survive beyond the neonatal period, the risk of developing Wilms tumor is approximately 64%.
WAGR syndrome
WAGR syndrome is caused by a deletion on chromosome 11 inclusive of both the WT1 and the PAX6 genes. PAX6 is associated with aniridia (absence of color in the iris), which is typically the first noticeable sign of WAGR. Wilms tumor due to WAGR occurs earlier than in isolated cases of Wilms tumor and is more often bilateral. Intellectual disability is common, as are psychiatric and behavioral problems. The most common genitourinary anomaly in males is cryptorchidism. Females may have underdeveloped ovarian tissue and bicornuate uterus, leading to fertility issues.
Denys-Drash syndrome (DDS)
DDS is the result of pathogenic variants in the WT1 gene. This condition primarily 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 manifest only the renal features of DDS and have normal genitalia, they are often diagnosed with isolated nephrotic syndrome.
Frasier syndrome
Like DDS, Frasier syndrome is the result of pathogenic variants in WT1 and 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 manifest only the renal features and have normal genitalia and gonads, 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.
CDC73-related conditions include familial isolated hyperparathyroidism (FIHP), parathyroid carcinoma, and hyperparathyroidism-jaw tumor (HPT-JT) syndrome. FIHP and hereditary parathyroid carcinoma lack additional extra-organ involvement, but HPT-JT is typically a multi-systemic neoplastic condition. Features include primary hyperparathyroidism due to parathyroid adenoma or carcinoma, ossifying fibroma(s) of the maxilla and/or mandible, and renal lesions including cysts, hamartomas and Wilms tumor.
The genes on this panel are associated with hereditary Wilms tumor, but the overall percentage of hereditary cancer cases caused by these risk factors is currently unclear. Inclusion of multiple Wilms-related genes is expected to increase the clinical sensitivity of this test.
Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. For gene-associated cancer risks, see the table below.
Condition | Wilms tumor | Gonadoblastoma | References (PMIDs) |
---|---|---|---|
Non-syndromic WT1 pathogenic variants | elevated | 12193442, 25688735 | |
WAGR syndrome | 40%–50% | 11479730, 11920832 | |
Denys-Drash syndrome | 90% | 40% | 15150775, 8827067, 25623218, 20301471 |
Perlman syndrome | 64% | 22306653 | |
Frasier syndrome | elevated | 60% | 25623218 |
Simpson-Golabi-Behmel syndrome | elevated | elevated | 16398453 |
Beckwith-Wiedemann syndrome | up to 8% | 12138139 | |
CDC73-related conditions | elevated | 7912571, 7717405 | |
REST-associated Wilms tumor | elevated | 26551668, 9771705 |
Elevated: There is evidence of association, but the penetrance and risk are not well characterized.
Isolated and syndromic causes of Wilms tumor can have different inheritance patterns depending on the gene:
Wilms tumor affects 1 in 8,000–10,000 children in North America. It is the most common pediatric kidney cancer and accounts for 6.3% of all cancers in children under age 15.
This panel may be considered for individuals with a personal and/or family history of:
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 |
---|---|---|---|
CDC73 | NM_024529.4 | ||
CDKN1C | NM_000076.2 | ||
CTR9 | NM_014633.4 | ||
DIS3L2 | NM_152383.4 | ||
GPC3* | NM_004484.3 | ||
REST | NM_005612.4 | ||
WT1 | NM_024426.4 |
GPC3: Sequencing analysis for exons 3 includes only cds +/- 10 bp.