Saturday 9 February

1991

No 8737

ORIGINAL ARTICLES

Linked DNA markers for presymptomatic diagnosis of familial adenomatous polyposis

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symptom-free individuals aged 0-39 years who were at risk of familial adenomatous polyposis (FAP) were genotyped with six linked DNA probes. 28 individuals were informative for probes flanking the gene and 14 people assigned a probe-derived risk of over 0·93 were subsequently shown to be affected by clinical screening. 4 individuals who had been discharged from follow-up were designated high risk by this method. In those screened negative, risk was calculated from genotypic, colonic, and CHRPE findings and 89% of subjects had a risk below 0·003. An integrated risk analysis may have an important place in screening programmes for FAP.

Introduction The autosomal dominant gene responsible for familial adenomatous polyposis (FAP) was first mapped to the long arm of chromosome 5 by genetic linkage. 1,2 Further chromosome 5 markers that recognise DNA polymorphisms have been reported to be linked to F AP3--S and a high-resolution linkage map that includes loci recognised by six DNA probes located close to, and on both sides of the FAP gene has been described.6 The offspring of patients with FAP have a 50% chance of inheriting the gene defect. Screening by regular large-bowel endoscopy is

recommended from puberty until 30 years of age but should probably continue until 60 years of age.’ Marker probe analysis of DNA purified from a single blood sample could provide a simple method of presymptomatic screening for FAP in suitable families. The inherent inaccuracy of a probe is measured by the recombination fraction. If this fraction is 5% between a probe and a gene then the probe will predict disease status correctly in 95% of tests. Linked markers therefore give an assessment of risk, not an absolute diagnosis. Risk estimation can approach 100% if markers map to both sides of the gene (flanking markers). A completely inaccurate risk assessment, despite informative flanking markers, could only take place with simultaneous recombinations between both markers and the gene concerned. The application of probes linked to the FAP gene could allow risk estimation in those individuals without clinical evidence of disease and might reduce the frequency of screening procedures for those at low risk. High-risk subjects could be screened ADDRESSES University of Edinburgh Department of Clinical Surgery (M. G. Dunlop, FRCS), Royal Infirmary, Edinburgh, UK; Cancer Research Campaign Laboratories (A H. Wyllie, FRCPath, J. Piris, MRCPath), Department of Pathology, Edinburgh University Medical School, Teviot Place, Edinburgh; and Medical Research Council Human Genetics Unit (C. M. Steel, FRCP, H. J Evans, PhD), Western General Hospital, Crewe Road, Edinburgh. Correspondence to Mr M G Dunlop, MRC Human Genetics Unit, Western General Hopsital, Crewe Road, Edinburgh EH4

2XU, UK.

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TABLE I-RISK ASSESSMENT

P= p1227, C = C11 P11, EC=ECB27, L= L5 62, EF= EF5 44, Y = YN5.48 is the same as probe-derived risk unless previous risk was

Combined risk

Linked DNA markers for presymptomatic diagnosis of familial adenomatous polyposis.

41 symptom-free individuals aged 0-39 years who were at risk of familial adenomatous polyposis (FAP) were genotyped with six linked DNA probes. 28 ind...
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