Wilms Tumor via the WT1 Gene

Wilms tumor (WT1, OMIM 194070) is the most common pediatric kidney cancer. It affects nearly 8 in 1,000,000 children in the United States (Davidoff. 2009. Curr Opin Pediatr. 21(3):357). Clinical features of an affected individual can include an abdominal mass, pain, fever, anemia, hematuria, and hypertension. Most individuals present with unilateral kidney tumors. Approximately 5-10% of individuals present with bilateral or multifocal tumors of the kidneys. Wilms tumor usually presents before the age of five, but it has also been documented in adults. Although variants in the WT1 gene are responsible for isolated Wilms tumor, alterations in the gene are also responsible for WAGR syndrome (Wilms tumor, aniridia, genital anomalies, retardation), Denys-Drash syndrome, Frasier syndrome, and Wilms tumor with genitourinary (GU) anomalies without renal failure (Dome and Huff. GeneReviews. 2011.).

Wilms tumor can be caused by variants in WT1, a tumor suppressor that interacts with the Wnt/beta-catenin signaling pathway and many other downstream targets of cellular growth, differentiation, and apoptosis (Md Zin et al. Pathology 43(4):302, 2011). The Wilms tumor protein encodes a zinc finger transcription factor that is important in the development of the kidney and gonads. Variants in WT1 are inherited in an autosomal dominant manner with reduced penetrance and variable expressivity. Most variants occur de novo (Dome and Huff. GeneReviews. 2011). Types of variants reported to date include nonsense, missense, splice site, small insertions and deletions, and large deletions (Human Gene Mutation Database).

Most Wilms tumors have a sporadic cause; germline variants in WT1 are responsible for less than 20% cases of isolated Wilms tumors (non-syndromic; Zin et al. Pathology 43(4): 302-12, 2011). Most individuals with Denys-Drash syndrome have a germline WT1 missense variant in exon 8 or 9 (Martinez. et al. Adv Exp Med Biol. 685:196-209, 2010). Frasier syndrome is caused by point variants in the WT1 intron 9 donor splice site (Barbaux et al. Nat Genet 17:467-470, 1997). Large deletions are found in WAGR syndrome and infrequently in isolated Wilms tumor.

This test provides full coverage of all coding exons of the WT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.