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Presymptomatic diagnosis for neurofibromatosis 2 with chromosome 22 markers

Ludwig Institute for Cancer Research, Clinical Group (Drs. Ruttledge and Collins), and the Department of Clinical Genetics (Drs. Ruttledge, Dumanski, and Nordenskjöld), Karolinska Hospital, Stockholm, Sweden; the Centre for Human Genetics (Dr. Narod and J. Parboosingh), and the Department of Neurology (M-C. Faucher and Dr. Rouleau), Montreal General Hospital/McGill University, Montreal, Canada; the Clinical Epidemiology Branch (Dr. Parry), National Cancer Institute, Bethesda, MD; retired from the United States Public Health Service (Dr. Eldridge), National Institutes of Health. Bethesda, MD; the Department of Medical Genetics (Dr. Wertelecki), University of South Alabama, Alabama; the Unit for Mechanisms of Carcinogenesis (Dr. Lenoir), International Agency for Research on Cancer, Lyon, France; and the Department of Pathology I (Dr. Collins), Sahlgrenska Hospital, Gothenburg, Sweden.

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by multiple tumors of the central nervous system, predominantly bilateral vestibular schwannomas. The gene for NF2 is located in the chromosomal region 22ql2 between the loci D22S1 and D22S28. We have performed genetic linkage analysis on 13 NF2 families with a total of nine polymorphic DNA markers, including five which we have recently mapped to this region. Two loci, D22S32 and NEFH, are linked to the NF2 locus at 0% recombination (lod scores of 6.03 and 4.28, respectively). By multipoint linkage analysis, we assign the NF2 gene to an interval of 7 cM, between the loci D22S212 and D22S28. We have used this set of nine markers to construct chromosome 22 haplotypes for the 82 at-risk individuals in this pedigree set. It has been possible to determine, with a high degree of certainty, the carrier status of 70 (85%) of these at-risk individuals. Risk prediction was possible in every case where DNA was available from both parents. Fifty-three of the 70 (76%) informative individuals were assigned decreased risks of being carriers. The use of chromosome 22 probes for risk assessment should result in a greatly reduced number of individuals who require periodic screening for NF2.

Address correspondence and reprint requests to Martin H. Ruttledge, Department of Neurology, 7th Floor Livingston Hall. Montreal General Hospital, 1650 Cedar Avenue, Montreal, PQ H3G 1A4, Canada.

Supported by grants from the Swedish Cancer Fund, Ingabritt and Arne Lundbergs Foundation, Axel and Margaret Ax:son Johnsson Foundation, the Swedish Medical Research Council, the Torsten and Ragnar Söderbergs Foundation, the Medical Research Council of Canada, and the National Neurofibromatosis Foundation (NNFF). S.A.N, and G.A.R. are fellows of the Fonds de la Recherche en Santé du Québec. J.P.D. is a recipient of the Young Investigator Award from the NNFF.

Received September 16, 1992. Accepted for publication in final form January 12, 1993.

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