Population-based risk estimates of Wilms tumor in sporadic aniridia - A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia

Aniridia is a severe eye disease characterized by iris hypoplasia; both spo radic cases and familial cases with an autosomal dominant inheritance exist . Mutations in the PAX6 gene have been shown to be the genetic cause of the disease. Some of the sporadic cases are caused by large chromosomal deleti ons, some of which also include the Wilms tumor gene (WAGR syndrome), resul ting in an increased risk of developing Wilms tumor. Based on the unique re gistration of both cancer and aniridia cases in Denmark, we have made the m ost accurate risk estimate to date for Wilms tumor in sporadic aniridia. We have found that patients with sporadic aniridia have a relative risk of 67 (confidence interval: 8.1-241) of developing Wilms tumor. Among patients i nvestigated for mutations, Wilms tumor developed in only two patients out o f 5 with the Wilms tumor gene (WT1) deleted. None of the patients with smal ler chromosomal deletions or intragenic mutations were found to develop Wil ms tumor. Our observations suggest a smaller risk for Wilms tumor than prev ious estimates, and that tumor development requires deletion of WT1. We rep ort a strategy for the mutational analysis of aniridia cases resulting in t he detection of mutations in 68% of sporadic cases and 89% of familial case s. We also report four novel mutations in PAX6, and furthermore, we have di scovered a new alternatively spliced form of PAX6.