Familial adenomatous polyposis (FAP), an autosomal dominant inherited disease, confers a high risk of colon cancer, and recently the gene responsible for FAP, termed adenomatous polyposis coli (APC) gene, was identified and fully characterized. OBJECTIVE For the presymptomatic diagnosis of FAP, we have performed linkage studies using two polymorphic systems close to or at the APC locus; cytosine-adenine dinucleotide repeat length polymorphism and restriction endonuclease RsaI site polymorphism. RESULTS Based on the two polymorphic systems, we have determined the haplotype at the APC locus in 23 individuals of two Korean families with FAP. From these haplotypes of individuals, we could make the diagnosis, whether affected or unaffected, in 74 percent of 31 at-risk persons. To decrease the chance of misdiagnosis caused by recombinant events, the use of haplotypes was better than using one polymorphic system. In addition to polymorphic analysis, we have also searched germline mutations of the APC gene in eight individuals (26 percent of all 31 at risk persons) of another two FAP families which could not be diagnosed definitely by linkage analysis. A 5 base-pairs deletion at codon 1309 was detected in one of the families, and a 5 base-pairs deletion at codon 1185 was also identified in another family by using a ribonuclease protection assay followed by DNA sequencing. From these results, we could diagnose FAP with 100 percent accuracy. CONCLUSIONS Linkage studies by the RsaI site polymorphism and cytosine-adenine repeat length polymorphism as well as the polymerase chain reaction-based sequencing method provide accurate and efficient tools for presymptomatic diagnosis of FAP in their families.