Wilms tumor is the most common renal tumor of childhood, occurring with an incidence of 1 in 10,000 and with a median age of diagnosis between 3 and 4 years of age. Wilms tumours are thought to develop from abnormally persistent embryonal cells within nephrogenic rests (PMID: 19948536). The WT1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context (PMID: 1127846). The relationship between WT1 and Wilms tumor type 1 (autosomal dominant) was first reported in 1991 (Pelletier et al., PMID: 1654525). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven variants (nonsense, frameshift) in this gene reported in at least 8 probands in 3 publications (PMIDs: 15483024, 1654525, 18688870) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies, cell culture and mouse models (PMIDs: 2164159, 26035382, 21123950, 14645201). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism and phenotypic variability between Wilms tumor type 1 and congenital malformation syndromes associated with WT1 variants (Denys-Drash syndrome, Frasier syndrome, Meacham syndrome, and nephrotic syndrome, type 4). For example, many individuals with Denys-Drash syndrome harbor heterozygous missense variants in exon 8 or 9 and may act in a dominant-negative manner (Royer-Pokora et al., 2004; PMID: 15150775), while the majority of variants reported for Wilms tumor type 1 are loss-of-function variants. Therefore, we have split curations for WT1 into Wilms tumor type 1 and congenital malformation syndromes associated with variants in WT1. In summary, loss of function variants in WT1 are definitively associated with autosomal dominant Wilms tumor type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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