A study of how familial adenomatous polyposis (FAP) varies within families supports the hypothesis that modifier genes affect the severity of the disease. This in turn may provide new insights into tumour formation in the gut.

Severity of FAP was significantly related to truncation mutations of the APC gene. Individual family members with severe disease, associated with a high polyp count, had mutations clustering in the MCR region, and those with moderate or mild disease had mutations clustering in other regions of the gene.

Polyp counts showed a higher, significant, correlation for close relatives within a family than more distant relatives. The correlation coefficient, corrected for germline APC mutation, in sibling pairs was 0.42, for parent-sibling pairs was 0.29, and for more distant relatives was even weaker. Segregation analysis showed that a mixed model of inheritance not linked to the APC gene best fitted the data..

One hundred and sixty six patients from 55 families were studied. They had classic FAP and had had a prophylactic colectomy; 128 had known APC gene mutation. Counts of polyps in the colectomy samples were grouped by APC mutation indicating the genotype-phenotype relation, and correlation coefficients were calculated to assess variation within families independently of APC mutation, on the premise that closer relatives have more shared modifier genes.

FAP shows characteristic phenotypic variation, only some of which is due to APC gene mutations. The rest might be explained by a modifier gene or genes, as occurs in a mouse model.