Invitae Wilms Tumor Panel

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

Wilms tumor
(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. Several genes are associated with both syndromic and nonsyndromic forms of Wilms tumor, including CDKN1C, DIS3L2, GPC3 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 syndrome 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 (10424811, 11414765).

Simpson-Golabi-Behmel syndrome type 1 (SGBS1)
SGBS1 is a rare, X-linked overgrowth disorder that is a 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 a distinctive facies that includes macrocephaly, coarse facial features, macrostomia, and macroglossia. There is an increased risk for embryonal tumors, including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, and hepatocellular carcinoma (NCBI GeneReviews. Simpson-Golabi-Behmel Syndrome Type 1. Accessed September 2015).

Perlman syndrome
Perlman syndrome is a rare overgrowth condition that is the result of pathogenic variants in DIS3L2. This disorder is characterized by fetal/neonatal macrosomia, polyhydramnios, nephromegaly, distinctive facial appearance, developmental delay, renal dysplasia, nephroblastomatosis, and predisposition to Wilms tumor. The prognosis of Perlman syndrome is poor, with a high neonatal mortality rate. Among the infants who survive beyond the neonatal period, the risk of developing Wilms tumor is approximately 64% (22306653).

WAGR syndrome
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 this condition. Wilms tumor due to WAGR syndrome 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.

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.

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 can present differently, even among family members. Because we cannot predict which cancers may develop, most individuals who are found to have a pathogenic variant will be offered screening tests to detect and prevent cancer.

Isolated and syndromic causes of Wilms tumor can be inherited in different patterns depending on the gene:

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

Wilms tumor affects 1 in 8,000–10,000 children in North America (7680412). It is the most common pediatric kidney cancer and accounts for 6.3% of all cancers in children under age 15 (8001010). Most cases are sporadic, but approximately 10%–15% are due to a hereditary pathogenic variant in a disease-causing gene that may or may not be associated with a known syndrome.

• 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 and Frasier syndromes are rare; their exact prevalence is currently unknown.
• The prevalence of Perlman syndrome is currently unknown and appears to be rare.
• The prevalence of Simpson-Golabi-Behmel syndrome is currently unknown and appears to be rare.

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