title: Genetic screening for low-penetrance variants in protein-coding genes.
abstract: Genetic testing holds great promise as a screening tool to identify persons at risk for a disease at the presymptomatic stage. However, the complexities of gene-disease associations, even in single-gene diseases, pose important challenges. These challenges include defining the role of screening for mutations that have low penetrance, which cause disease in only a minority of patients with the genotype. On the basis of the high rate of false positives, medical expert panels to date have largely discouraged genetic testing for low-penetrance mutations for use in population-based screening, although official recommendations currently exist for only a few genes. We examine the relatively limited experience of population-based screening for low-penetrance mutations in clinical settings to date, including screening for glucose-6-phosphate dehydrogenase deficiency and a low-penetrance mutation for cystic fibrosis in newborns, type 1 Gaucher disease carrier screening, and screening for adults for hemochromatosis. The trend toward recommending restricting use of these tests by medical experts is contrasted with the growing availability of genetic tests, including those for low-penetrance mutations, through direct-to-consumer outlets.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. jwaalen@scripps.edu
authors.forename: Jill
authors.initials: J
authors.lastname: Waalen
authors.forename: Ernest
authors.initials: E
authors.lastname: Beutler
mesh_terms: D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000266:history; D014644:Genetic Variation; D049673:History, 20th Century; D006801:Humans; D009154:Mutation; D016366:Open Reading Frames; D019683:Penetrance