Improved predictive carrier testing for familial adenomatous polyposis using DNA from a single archival specimen and...

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition caused by mutations in a candidate tumor suppressor gene, adenomatous polyposis coli. Predictive carrier testing for FAP can be accomplished by DNA linkage or mutation detection analysis. In many FAP families all affected individuals are deceased. Archival tissue specimens, if available from such patients, are a useful source of DNA for molecular analysis. We investigated the carrier risk of a presymptomatic 5-year-old girl with a family history of FAP. An archival specimen of normal colonic tissue was only available from the proband's affected deceased father. We screened DNA extracted from this specimen with dinucleotide repeat (CA/GT)n polymorphic marker (D5S346) linked to the adenomatous polyposis coli gene and established that the proband is at more than 99% risk of developing FAP. The proband's increased risk status was subsequently confirmed by identification of a germline adenomatous polyposis coli gene mutation consisting of a 5 base pair deletion at codon 1061. This strategy of using DNA from archival specimens of affected, unavailable FAP patients will increase the number of at-risk individuals that can be diagnosed presymptomatically.