Screening by Genomic Linkage Studies and Mutation Analysis of Hereditary Adenomatous Polyposis Coli: Usefulness for Clinical Practice

Abstract

A heterogeneous group of patients suffering from adenomatous polyposis coli (APC) were evaluated by clinical and genetic investigations for the first time in Austria. The patients belonged to eight unrelated APC families. In six families several family members were affected with APC, and linkage analysis with highly informative markers was used to estimate the risk of single individuals in these families to develop APC. All index patients were also tested for the most frequent mutation in the APC gene (mutation cluster region, exon 15). Clinical investigations included ophthalmologic tests for congenital hypertrophy of retinal pigment epithelium and colonoscopy. According to DNA analysis, 5 of 19 at-risk individuals had to be considered to be at high risk of having inherited the disease. Four of them underwent proctocolectomy, one patient at risk is under colonoscopic surveillance. The predictive value of indirect genotype analyses reached 83.3%; direct mutation analyses allowed risk estimation in 50% of cases. Ophthalmologic investigation was informative in 75% of the families. Direct and indirect genotyping using a panel of highly polymorphic, closely linked microsatellite markers is a valuable, rapid, reliable method for establishing a presymptomatic diagnosis of APC, especially in families in which more than one affected individual is available for analysis. With regard to the onset of APC and extracolonic manifestations, the variability of APC demands clinical investigations in addition to the molecular tests for all patients and their first-degree relatives.

Quality in genetic counselling for presymptomatic testing — clinical guidelines for practice across the range of genetic conditions

“…4 Later, as understanding of familial cancer syndromes increased, PST was offered to individuals at increased risk of breast and ovarian cancer, 5 Lynch syndrome (previously termed hereditary nonpolyposis cancer) 6 and familial adenomatous polyposis. 7 The information now available about specific disease-causing mutations has enabled PST to be offered for a much wider range of disorders and it may now be provided by health professionals outside of specialist genetic centres. For example, testing for the mutations that cause hypertrophic cardiomyopathy, 8 or maturity onset diabetes of the young 9 may be offered in cardiac and diabetes clinics, respectively.…”