EVALUATION OF MOLECULAR-GENETIC DIAGNOSIS IN THE MANAGEMENT OF FAMILIAL ADENOMATOUS POLYPOSIS-COLI - A POPULATION-BASED STUDY

A population based clinical and molecular genetic study of familial ad enomatous 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 pat ients was 2.62 x 10(-5) (1/38 000) and the minimum heterozygote preval ence was estimated at 3.8 x 10(-5) (1/26 000). Eight of 33 (24%) proba nds were new mutations. Forty-eight asymptomatic relatives at 50% prio r risk aged between 10 and 40 years were assessed for risk modificatio n with linked DNA markers: in nine subjects (18%) the family structure was unsuitable for linkage based analysis, but 32 subjects were infor mative 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 re latives and 0/18 low risk relatives had more than three CHRPEs. Interf amilial variation in CHRPE expression was apparent. This study has sho wn 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 s tudy) means that molecular genetic diagnosis of FAPC is a cost effecti ve procedure.