Hum Genet (1991) 86:365-368 9 Springer-Verlag 1991 A new deletion polymorphism at D5S71 raises the linkage information on adenomatous polyposis coli: implications for presymptomatic diagnosis C. M. J. Tops 1, C. Breukel 1, H.M. van der Klift I, I. S. J. v. Leeuwen 1' 2, j.T. Wijnen 1, G. Griffioen 3 , H. F. A. Vasen 2' 3, E C. A. den Hartog Jager 4, E M. Nagengast 5, C. B. H. W. Lamers 3, and P. Meera Khan 1 1Human GeneticsInstitute, Universityof Leiden, P.O. Box 9503, NL-2300RA Leiden, The Netherlands 2 National PolyposisRegistration Center, Foundationfor the Detection of Hereditary Tumours, and 3 Department of Gastroenterology, UniversityMedical Centre, NL-2300 RA Leiden, The Netherlands 4Netherlands Cancer Institute and Department of Gastroenteroloy,AcademicMedicalCentre, Plesmanlaan121, NL-1066 CX Amsterdam, The Netherlands 5Department of Gastroenterology,UniversityHospital, G. Grootte Plein Zuid 8, NL-6525 GA Nijmegen,The Netherlands Received May 14, 1990 / Revised August 28, 1990 Summary. Two independent study-groups, one in Bri- tain and the other in the United States, were the first to report linkage between APC and a TaqI restriction frag- ment length polymorphism (RFLP) at D5S71 (probe Cllp11) on chromosome 5q. They found no recombin- ants in about 50 informative meioses. The same TaqI RFLP was found to be uninformative for linkage in 15 Dutch polyposis families. The recently reported four base-pair deletion polymorphism (DELl) at D5S71 has raised the polymorphism information content of this marker from 0.17 to 0.40 in the Dutch population. Seven of 20 polyposis families screened for the DELl as well as the TaqI polymorphism gave a combined peak lod score of 5.68 with no recombinants in 37 informative meioses. These data, together with those so far reported in the lit- erature, raise the peak lod score to 17.09 at a recombina- tion fraction of 0.05, the 95% upper confidence limit being 0.09. In combination with the use of another infor- mative marker, D5S81 (probe YN5.48) closely mapping on the other side of APC, the presymptomatic diagnosis of the disease can be made with more than 99.9% cer- tainty. It has to be stressed, however, that the the possi- ble existence of more than one polyposis locus cannot, as yet, be excluded. Introduction Adenomatous polyposis coli (APC), also known as fa- milial polyposis coli (FPC) and familial adenomatous polyposis (FAP), is a dominantly inherited autosomal condition. The APC gene exhibits complete penetrance, and determines predisposition to colorectal carcinoma Offprint requeststo: C. M. J. Tops (Bussey 1975). The age at clinical diagnosis is variable and first-degree relatives have, a priori, a 50% risk of carrying the disease gene. Since the localization of the APC gene on chromosome 5, several probes linked to APC have been identified. The first marker recognized as linked to APC is the single-copy genomic DNA probe called Cllp11, the corresponding locus symbol being D5S71 (Bodmer et al. 1987; Leppert et al. 1987). Pre- liminary studies by in-situ hybridization have localized Cllpll to the 5q21-q22 chromosome region (Bodmer et al. 1987). The studies of Bodmer et al. (1987) and Lep- pert et al. (1987) revealed no recombinants between D5S71 and APC in about 50 informative meioses in eight families. Recently, three obligate recombinants were found, in four additional informative families, by other investigators in Britain (Aldred et al. 1988; Dunlop et al. 1989). The above results were based upon a TaqI restric- tion fragment length polymorphism (RFLP) at D5S71, with a polymorphism information content (PIC value) estimated to be about 0.17 in the Dutch population. How- ever, by screening 15 apparently independent Dutch polyposis families, we found only a two-child nuclear family to be informative for linkage between the TaqI RFLP site at D5S71 and APC (Meera Khan et al. 1988). During an explicit search for base sequence variations at D5S71 we identified a four-base deletion polymorphism, designated DELl, in a sequenced stretch of 498 base pairs within D5S71. DELl screening can be completed within 2 days after blood collection using less than 500 ng of DNA per test and it does not require radio-isotope labelling. The use of the DELl polymorphism has raised the PIC value of Cllpll from 0.17 to 0.40 (Breukel et al. 1989a, b). In this study we screened 20 Dutch poly- posis families for TaqI as well as DELl polymorphism at D5S71 and used the resultant TaqI-DEL1 haplotypes for estimating linkage between D5S71 and APC.