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  • Test code: 01742
  • 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
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Invitae Wilms Tumor Panel

Test description

The Invitae Wilms Tumor Panel analyzess 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 5 genes associated with Wilms tumor. In addition to the primary panel, clinicians can also choose to include 2 genes that have preliminary evidence of an association with this cancer type. At this time, the association of these genes with Wilms tumor remains uncertain; however, some clinicians may wish to include genes that may prove to be clinically significant in the future. These genes 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.

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Primary panel (5 genes)
Add-on Preliminary-evidence Genes for Wilms tumor (2 genes)

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 REST

Alternative tests to consider

These genes can also be ordered as part of a broader panel to test for hereditary cause 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.

  • Beckwith-Wiedemann syndrome (BWS)
  • CDC73-related conditions
  • Perlman syndrome
  • Simpson-Golabi-Behmel syndrome
  • WT1-related disorders
    • Denys-Drash syndrome (DDS)
    • Frasier syndrome
    • WAGR syndrome (wilms, aniridia, genitourinary, retardation)
    • isolated, nonsyndromic Wilms tumor

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.

ConditionWilms tumorGonadoblastomaReferences (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

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:

  • CDC73, CDKN1C and WT1: autosomal dominant
  • DIS3L2: autosomal recessive
  • GPC3: X-linked

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.

  • WAGR syndrome occurs in 1 in 500,000 to 1 in one million individuals. Approximately one-third of those diagnosed with aniridia have underlying WAGR and roughly 1 in 143 cases of Wilms tumor are due to WAGR.
  • Beckwith-Wiedemann syndrome occurs in approximately 1 in 13,700 individuals.
  • Denys-Drash, Frasier, Perlman, Simpson-Golabi-Behmel, and CDC73-related conditions are rare; their exact prevalence is currently unknown.

This panel may be considered for individuals with a personal and/or family history of:

  • Wilms tumor
  • findings such as developmental delay, macrosomia, dysmorphic craniofacial features, cardiac, gastrointestinal, and genitourinary anomalies suggestive of an underlying syndrome

  1. Golabi, M, et al. Simpson-Golabi-Behmel Syndrome Type 1. 2006 Dec 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1219/ PMID: 20301398
  2. Morris, MR, et al. Perlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2. Am J Med Genet C Semin Med Genet. 2013; 163C(2):106-13. PMID: 23613427
  3. Dome, JS, Huff, V. Wilms Tumor Overview. 2003 Dec 19. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301471
  4. Goldman, M, et al. Renal abnormalities in beckwith-wiedemann syndrome are associated with 11p15.5 uniparental disomy. J. Am. Soc. Nephrol. 2002; 13(8):2077-84. PMID: 12138139
  5. Pritchard-Jones, K. Controversies and advances in the management of Wilms' tumour. Arch. Dis. Child. 2002; 87(3):241-4. PMID: 12193442
  6. Gracia, Bouthelier, R, Lapunzina, P. Follow-up and risk of tumors in overgrowth syndromes. J. Pediatr. Endocrinol. Metab. 2005; 18 Suppl 1:1227-35. PMID: 16398453
  7. Kaneko, Y, et al. A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation. Br. J. Cancer. 2015; 112(6):1121-33. PMID: 25688735
  8. Cohen, MM. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives. Pediatr. Dev. Pathol. 2005; 8(3):287-304. PMID: 16010495
  9. Astuti, D, et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat. Genet. 2012; 44(3):277-84. PMID: 22306653
  10. DeBaun, MR, et al. Nephromegaly in infancy and early childhood: a risk factor for Wilms tumor in Beckwith-Wiedemann syndrome. J. Pediatr. 1998; 132(3 Pt 1):401-4. PMID: 9544890
  11. Breslow, N, et al. Epidemiology of Wilms tumor. Med. Pediatr. Oncol. 1993; 21(3):172-81. PMID: 7680412
  12. Miller, RW, et al. Childhood cancer. Cancer. 1995; 75(1 Suppl):395-405. PMID: 8001010
  13. Ezaki, J, et al. Gonadal tumor in Frasier syndrome: a review and classification. Cancer Prev Res (Phila). 2015; 8(4):271-6. PMID: 25623218
  14. Lam, WW, et al. Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J. Med. Genet. 1999; 36(7):518-23. PMID: 10424811
  15. Li, M, et al. Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. Genomics. 2001; 74(3):370-6. PMID: 11414765
  16. Grønskov, K, et al. Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum. Genet. 2001; 109(1):11-8. PMID: 11479730
  17. Muto, R, et al. Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am. J. Med. Genet. 2002; 108(4):285-9. PMID: 11920832
  18. American Cancer Society, cancer.org: What are the risk factors for Wilms tumor? http://www.cancer.org/cancer/wilmstumor/detailedguide/wilms-tumor-risk-factors Accessed August 2018.
  19. Charlton, J, et al. Bilateral Wilms tumour: a review of clinical and molecular features. Expert Rev Mol Med. 2017; 19:e8. PMID: 28716159
  20. van, Heyningen, V, et al. Raised risk of Wilms tumour in patients with aniridia and submicroscopic WT1 deletion. J. Med. Genet. 2007; 44(12):787-90. PMID: 17630404
  21. Breslow, NE, et al. Characteristics and outcomes of children with the Wilms tumor-Aniridia syndrome: a report from the National Wilms Tumor Study Group. J. Clin. Oncol. 2003; 21(24):4579-85. PMID: 14673045
  22. Royer-Pokora, B, et al. Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am. J. Med. Genet. A. 2004; 127A(3):249-57. PMID: 15150775
  23. Mueller, RF. The Denys-Drash syndrome. J. Med. Genet. 1994; 31(6):471-7. PMID: 8071974
  24. Jaubert, F, et al. Gonad development in Drash and Frasier syndromes depends on WT1 mutations. Arkh. Patol. 2003; 65(2):40-4. PMID: 15357247
  25. Li, M, et al. GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome. Am. J. Med. Genet. 2001; 102(2):161-8. PMID: 11477610
  26. Cottereau, E, et al. Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature. Am J Med Genet C Semin Med Genet. 2013; 163C(2):92-105. PMID: 23606591
  27. Alessandri, JL, et al. Perlman syndrome: report, prenatal findings and review. Am. J. Med. Genet. A. 2008; 146A(19):2532-7. PMID: 18780370
  28. Brioude, F, et al. Beckwith-Wiedemann syndrome: growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance. Horm Res Paediatr. 2013; 80(6):457-65. PMID: 24335096
  29. Gizewska, M, et al. The significance of molecular studies in the long-term follow-up of children with beckwith- wiedemann syndrome. Turk. J. Pediatr. 2014; 56(2):177-82. PMID: 24911853
  30. Kakinuma, A, et al. Familial primary hyperparathyroidism complicated with Wilms' tumor. Intern. Med. 1994; 33(2):123-6. PMID: 7912571
  31. Szabó, J, et al. Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am. J. Hum. Genet. 1995; 56(4):944-50. PMID: 7717405
  32. Bricaire, L, et al. Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 2013; 98(2):E403-8. PMID: 23293331
  33. Wang, O, et al. Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas. PLoS ONE. 2012; 7(9):e45567. PMID: 23029104
  34. Carpten, JD, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat. Genet. 2002; 32(4):676-80. PMID: 12434154

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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

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