Novel truncating WT1 germline variant in a case of familial Wilms tumor

Wilms tumor (WT) is the most common pediatric renal tumor. Familial WT represents 1-2% of individuals with WT and is associated with increased risk of bilateral tumors, congenital anomalies of the kidney and urinary tract, disorders of sexual development, and other malformations. Wilms tumor etiology is heterogeneous, yet several monogenic causes have been identified including WT1 alterations. A 4-year-old boy presented with unilateral WT and a family history of WT. The proband's mother and her monozygotic twin were both treated for metachronous WTs at 9 and 10 months of age, with second primary at 33 and 30 months of age, respectively. The mother's twin died 34 months old. The boy underwent surgery, and histopathology revealed a mixed type, intermediate-risk group, stage II tumor. He received pre- and post-operative chemotherapy. A novel germline truncating heterozygous WT1 variant (c.634G>T, p.(Glu212Ter)) in exon 1 was identified in blood and a second WT1 hit was identified in the tumor (c.856C>T, p.(Gln286Ter)) in exon 3 using whole genome sequencing. Genetic testing of the family members identified the germline variant in the mother but not in the maternal grandparents. It was not possible to test the mother's twin. Additionally, we provide an overview of all reported WT1 germline variants described in Clinvar and HGMD in individuals with WT. The presence of a germline WT1 variant increases the risk of intralobar nephrogenic rests, bilateral WT, typically with onset at an earlier age. Because of this elevated and distinct risk profile management differs from that of sporadic WT.