Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypiccharacteristics of Wilms' tumour attributable to FWT1

A susceptibility gene for Wilms' tumour (WT), designated FWT1, was previous ly mapped to chromosome 17q12-q21 by linkage analysis of a single family. W e now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evid ence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms t hat there is genetic heterogeneity in familial WT, as three families exhibi t strong evidence against linkage to FWT1. One of these was subsequently fo und to have a predisposing WT1 mutation. However, the other two families sh ow evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confir m the role of FWT1 in susceptibility to WT, provide strong evidence for gen etic heterogeneity in familial WT and suggest there are phenotypic differen ces between familial WT due to FWT1, familial WT due to other genes and non -familial WT.