Abstract

A population based clinical and molecular genetic study of familial adenomatous polyposis coli (FAPC) was performed to investigate the value of molecular genetic analysis and ophthalmological assessment in the presymptomatic diagnosis of FAPC. The point prevalence of affected patients was 2.62 x 10(-5) (1/38,000) and the minimum heterozygote prevalence was estimated at 3.8 x 10(-5) (1/26,000). Eight of 33 (24%) probands were new mutations. Forty-eight asymptomatic relatives at 50% prior risk aged between 10 and 40 years were assessed for risk modification with linked DNA markers: in nine subjects (18%) the family structure was unsuitable for linkage based analysis, but 32 subjects were informative with a panel of intragenic and closely linked markers (25 had a combined age/DNA related risk of < 1% (low risk group) and seven were at high risk (DNA predicted risk > 99%)). Ophthalmological assessment for CHRPEs showed that 27/43 (63%) affected patients and high risk relatives and 0/18 low risk relatives had more than three CHRPEs. Interfamilial variation in CHRPE expression was apparent. This study has shown that DNA based risk modification with intragenic and closely linked DNA markers is informative in most FAPC families. In addition to the clinical benefits of presymptomatic diagnosis for FAPC, the reduction in screening for low risk relatives (365 person years in the present study) means that molecular genetic diagnosis of FAPC is a cost effective procedure.