Wilms Tumor 6
A number sign (#) is used with this entry because of evidence that susceptibility to Wilms tumor can be caused by mutation in the REST (600571) gene on 4q12.
For a general phenotypic description and discussion of genetic heterogeneity of Wilms tumor, see WT1 (194070).
Molecular GeneticsTo identify predisposition genes for Wilms tumor, Mahamdallie et al. (2015) performed exome sequencing in 24 individuals with Wilms tumor from 12 families and identified 2 different frameshift mutations (600571.0001, 600571.0002) that segregated with the disease in 2 unrelated families. Neither was present in the ICR1000 and ExAC browsers. The mutations were confirmed by Sanger sequencing. Subsequently, Mahamdallie et al. (2015) performed Sanger sequencing of the full coding sequence and intron-exon boundaries of the REST gene in 38 individuals with familial Wilms tumor from 27 families. They identified 2 missense mutations (e.g., H322R, 600571.0003) that were plausibly pathogenic on the basis of segregation with disease, absence from the ICR1000 and ExAC browsers, and predicted effect on REST function. Finally, Mahamdallie et al. (2015) sequenced 519 individuals with Wilms tumor and no family history of the disease. They identified 9 additional REST mutations that were considered pathogenic: 6 truncating mutations and 3 nonsynonymous mutations mapping to the DNA binding domain. Two of the mutations had been identified in familial Wilms tumor pedigrees, but there was no known relationship between these independently ascertained families. All tested variants showed abrogation of REST function. In 4 cases for whom parental DNA was available, 1 mutation had occurred de novo and 3 had been inherited, confirming incomplete penetrance. In summary, Mahamdallie et al. (2015) identified REST mutations in 16 individuals from 4 families and 9 nonfamilial Wilms tumor pedigrees. Ten of the 11 different mutations, including all of the nonsynonymous mutations, clustered in the DNA binding domain of REST. None was present in ICR1000 exome series of 993 or in the 61,312 individuals in the ExAC browser. Mahamdallie et al. (2015) concluded that their data established REST as a Wilms tumor predisposition gene accounting for approximately 2% of Wilms tumors, and recommended screening of REST in all familial cases.