Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes.

BACKGROUND Familial adenomatous polyposis (FAP) is characterised by variable phenotypic expression. Part of this is attributable to a relationship between APC genotype and phenotype but there remains significant intrafamilial variation. In the Min mouse model of FAP, differences in the severity of gastrointestinal polyposis result from the action of modifier genes. AIMS To determine whether phenotypic variation in human FAP has an inherited component consistent with the action of modifier genes. METHOD We systematically examined polyp numbers in colectomy specimens from patients with classical FAP. Variation both between and within families was analysed. Formal modelling of the segregation of disease severity in families was performed RESULTS There was strong evidence for a relationship between site of mutation and the number of colorectal polyps, with germline mutations in the "cluster region" causing the most severe disease and those with mutations between codons 1020 and 1169 having the mildest disease. In addition to this genotype-phenotype relationship, we found evidence for non-APC linked genetic modifiers of disease expression. First degree relatives had more similar polyp counts than more distant relatives. Formal modelling of the segregation of disease severity in families revealed further evidence for the action of modifier genes, with a best fit to a mixed model of inheritance. CONCLUSION Our data provide good evidence to support the hypothesis that modifier genes influence the severity of FAP in humans.