Direct genetic testing for Smad4 mutations in patients at risk for juvenile polyposis

Background. The identification of germline mutations in juvenile polyposis (JP) families has made presymptomatic genetic testing possible, In this stu dy we report the results of genetic testing in two large JP families and de velop an algorithm for the clinical management of these patients. Methods. DNA was extracted from 55 members of 2 JP kindreds, and the Smad4 mutations in the germline were determined by direct sequencing. All family members were then tested for mutations with use of single-strand conformati onal polymorphism analysis and were invited for genetic counseling. Results. All 18 affected members of both kindreds had a 4-bp deletion in ex on 9 of the Smad4 gene. In 30 patients at risk for JP, 17 had previously ha d negative endoscopic screening results and 13 had never been screened. Fiv e patients at risk had inherited germline Smad4 mutations. Two carriers hav e had hematochezia but have not been screened, whereas 3 were asymptomatic. The mean age of carriers was 29.8 years (range 9.1-49.5 years), whereas th at of noncarriers was 41.0 years (range 8.1-76.5 years). Conclusions. Compliance has been a problem with endoscopic screening for JP . With genetic testing noncarriers may no longer require frequent screening endoscopy,: whereas gene carriers can be targeted for close endoscopic sur veillance and early intervention to prevent the development of gastrointest inal cancers. Direct genetic testing significantly improves the presymptoma tic diagnosis of gene carriers in JP families with Smad4 mutations.