WT1 associated congenital malformation syndromes include Denys-Drash syndrome (DDS), Frasier syndrome, Meacham syndrome, and nephrotic syndrome, type 4. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that these congenital malformation syndromes have similar or overlapping clinical features and share a postulated dominant-negative mechanism. Therefore, we have lumped curations of these congenital malformation syndromes associated with WT1 into DDS, in which they are part of a spectrum and not distinct conditions although Wilms Tumor is more frequent in DDS than in Frasier syndrome. Of note, the WT1 gene has also been implicated in Wilms tumor type 1 which results from loss of function variants and a high risk of Wilms Tumor and was curated separately. WT1 is composed of ten exons and encodes a protein with four zinc-finger motifs with both transcriptional and tumor suppressor activities. WT1 was first reported in 10 patients affected by Denys-Drash syndrome in 1991, where heterozygous constitutional variants in WT1 were found in all tested affected individuals (PMID: 1655284). Variants in the WT1 gene have been identified in >95% of DDS patients (PMID: 1655284). The most commonly seen WT1 variant in DDS is the missense variant WT1 R394W, which is critical for interaction with a guanine in the DNA target. An alternative splice site in intron 9 allows the addition of 3 amino acids (KTS) between the third and fourth zinc fingers of the WT1 protein, resulting in the so-called +KTS isoform. Patients with Frasier syndrome specifically have unique variants in the donor splice site of intron 9 of the WT1 gene with a predicted loss of the +KTS isoform (PMID:9398852). Nine probands with DDS in four publications 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 mouse models, biochemical function and functional alteration studies (PMID:11278460, 1655284, 10077614, 15509792). In summary, WT1 is definitively associated with the autosomal-dominant (AD) Denys-Drash syndrome, Frasier syndrome and related disorders. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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