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D. Wangl, R. Sapolsky2,1, Spencer.1, T. Riouxl, L Session 20: Plenary Session A3 1 2 Genome-wide screen for Hirschsprung disease susceptibility loci in a Correction of the high-SCE phenotype in Bloom's syndrome (BS) cells Mennonite kindred segregating an endothelin-B receptor mutation. by transfection of the wild-type gene. J. German. M. Proytcheva. T.-Z. Ye. E.G. Puffenberger. A. Lynn, C. Kashuk, and A. Chakravarti. Dept. of Genetics, Case M. Sanz. N. Neff. N. A. Ellis. New York Blood Center, New York, NY. Weserin Reserve Univ., Cleveland, OH. BS is a rare autosomal recessive disorder characterized bv short stature and Genome-wide screens using polymorphic markers in segregating multiplex families are predisposition to developing cancer. An excessive rate of sister-chromatid exchanges now routine for localizing disease genes. In principle, susceptibility loci may even be (SCEs) in proliferating BS cells is a unique and diagnostic feature of the syndrome. mapped in simplex families by searching for allelic associations between genetic Recently, the BS gene, BLM, was isolated and shown to encode a 1417 amino acid markers and disease phenotype. This exercise is most efficient in isolated populations protein product homologous to RecQ helicases (Ellis et aL, 1995). We have introduced where large genomic segments will be shared by affected individuals on the basis of the wild-type BLM cDNA into BS cells in order to test its ability to correct the high- common ancestry. We demonstrate the identification of multiple genomic regions that SCE phenotype of BS cells. harbor putative susceptibility loci for Hirschsprung disease (HSCR) in a large, inbred A full-length BLM cDNA, R 12, was transferred into pOPRSVI-CAT, a mammalian Mennonite kindred by using genome-wide association mapping. We previously expression vector that contains the RSV promoter and dominant selectable marker neor. demonstrated the segregation of a missense mutation (W276C) in the endothelin-B The recipient cell line was the SV40-transformed fibroblast cell line GM08505B, which receptor gene (EDNRB) on chromosome 13q22 in this kindred. This mutation is derived from an Ashkenazi Jewish person with BS who is homozygous for a 6 bp demonstrated a sex and dosage dependent penetrance consistent with the complex deletionl7 bp insertion that results in termination at amino acid residue 740. Levels of pattern of inheritance of HSCR in the Mennonites. BLM mRNA in GM08505B are reduced and protein is undetectable by Western blot We analyzed the genotypes of 527 autosomal and X-linked microsatellite markers in analysis (Neff et al., this meeting). The SCE rate in GM08505B is high (mean 55.0 33 simplex HSCR cases and their parents. For each locus, associations between allele SCEs/46 chromosomes and range 15.9-88.4 SCEs/46 chromosomes of 20 cells). frequencies on the transmitted (T) and untransmitted (U) chromosomes were evaluated Ten micrograms of control cDNA, pOPRSVI-CAT, and of BLM cDNA, pOPRSVI- by chi-square statistics and multipoint association lod scores across each chromosome. R12, each were introduced by lipofection into GM08505B. Forty-eight hours after These analyses were repeated for chromosomes transmitted to affected W276C transfection, Geneticin selection was applied, clones were isolated and expanded, and heterozygotes (Ti) only. the SCE test was carried out. The SCE rate in cells transfected with the control cDNA The genome-wide screen for linkage disequilibrium identified several statistically sig- (I clone examined) was unchanged (mean 64.8; range 40.4-95.6; 20 cells) compared to nificant genomic regions in T and TI patient samples. As expected, a large region on that in untransfected GM08S05B cells, whereas the SCE rate in cells transfected with chromosome 13q22 (EDNRB) and a smaller region on chromosome 10qil (RET) were the BLM cDNA (2 clones examined) was corrected towards normal (mean 17.7; range detected in both T and Ti samples. No other statistically significant regions were identi- 8.5-41.0; 20 cells; and mean 18.0; range 10.3-25.4; 17 cells). fied in the total sample (T). However, when affected W276C heterozygotes were analyzed This phenotypic correction of GM08505B proves that the BLM cDNA encodes a independently, two other chromosomal segments were identified, viz. chromosome 6p and functional protein capable of complementing the high-SCE phenotype, and presumably 8q. The 8q locus barely exceeded the multipoint lod score threshold, while the 6p lo- the BS defect. This transfection system serves as a starting point for characterization of cus yielded results second in magnitude to EDNRB. Both of these loci are being studied the effects of mutations that we will introduce into the BLM cDNA in vitro and is the with additional markers in order to determine their role in the development of Mennonite first step toward therapy of the BS defect using the wild-type BLM gene. HSCR. 3 4 Coverage of new genetic technologies: What matters to insurers? M. Schoonmaker, B. Toward a third generation genetic map of the human genome Bernhardt and N.A. Holtzman. Johns Hopkins Medical Institutions. Baltimore, MD. based on bi-allelic To examine the role of third party payers in the diffusion of new genetic technologies, we polymorphisms. surveyed 751 insurance companies. 166 (22%) responded to a questionnaire using scenarios D. Wangl, R. Sapolsky2,1, Spencer.1, T. Riouxl, L. KruglyAkl, L to assess how coverage decisions would be made for cystic fibrosis carrier screening (CFCS), Hubbe[I2, G. Ghandg2, T.; Hawkjls1, T. Hudson1, R. Lipshut2 and BRCAl testing, and gene therapy for CF (GTCF). 76% have never made a coverage decision E. Lander1. 1Whitehead Institute/MIT Center for Genome for CFCS. 39% of insurers would cover the baseline scenario of offering CFCS to all pregnant Research, Cambridge, MA 02139 and Inc., Santa Clara, CA women at a cost of $40 per test and a sensitivity of 85%. Changing the scenario to only 2Affymetrix, 77% of 95051; pregnant women with a positive family history would result in coverage by companies. and studies a decreased endorsement ACOG and a demand would Large-scale genetic mapping epidemiology require Increased test sensitivity, cost, by high and robust for at hundreds of each also significantly increase coverage. For BRCA1 testing, 85% have never made a rapid technology assessing genotypes polymorphic loci in parallel. We have begun the construction of a coverage decision. 26% would cover a baseline scenario of testing high risk women using a of bi- $250 test detecting 80% of BRCA1 mutations. Changes significantly increasing the proportion third generation genetic map of the human genome consisting covering include an improved detection rate, reduced cost, endorsement by a national consensus allelic single nucleotide polymorphisms (SNPs) and the development conference and high consumer demand. For GTCF, 27% would cover the baseline scenario of a high-density DNA probe array for human genotyping. Bi-allelic of paying the medical costs of a trial of presymptomatic children. Coverage would be SNPs offer the advantages of ease of isolation (because of their great significantly more likely if therapy was offered only to severely affected children or adults, if abundance), highly parallel detection (using DNA probe arrays), and its effectiveness was proven, or if administered in a regional hospital or outpatient setting. automated scoring (because of their plus-minus nature). There were no differences in coverage of any technology by type of insurer (HMO, PPO, To identify SNPs, we have developed a semi-automated system for indemnity or self-insured payers). 36% thought patient demand for CFCS would be high, comparative sequencing of random PCR products from multiple versus 66% for BRCA1 testing and 91% for GTCF. Only 27% agreed that there is great unrelated individuals. Based on our results to date, SNPs with the potential for future cost savings in covering BRCA1 testing, versus 42% for CFCS and 58% minor allele a > 30% to occur at a rate of for GTCF. Fewer than 20% that for of these would having frequency appear agreed offering coverage any technologies 1/1000 To date, we have identified and more than 400 make their benefits policy more competitive. bp. mapped We conclude that few insurers have for coverage of selected new SNPs. developed policies genetic a of 1000-2000 well- technologies. Improvement in the sensitivity of testing, limiting tests to populations at highest Analysis shows that genetic map consisting risk, increased public demand, endorsement of technologies by professional societies, and spaced SNPs should suffice for comprehensive coverage in genetic reduced cost could lead to a greater likelihood of coverage. mapping studies. 5 6 Exoni of the Huntington's disease gene carrying highly expanded CAG Uptake and impact of BRCA1 testing in members of hereditary breast-ovarian repeats is sufficient to generate a progressive neurological phenotype in cancer (HBOC) families. C. Lerman, Georgetown University Medical Center. transgenic mice. G. Batesl. L. Mlangiarinil. K. Sathasivaml, \1. Seller', A. Harper2, Washington. DC; S. Narod, Women's College Hospital, Toronto, Ontario, Canada; and Y. Trottier3, J.-L. Mandel3 and S. Davies4. 1. Guys Hospital, UMIDS, London, UK. 2. H. Lynch, Creighton University, Omaha, Nebraska. St. Thomas's Hospital, UNIDS, London, UK. 3. IGBMIC, Strasbourg, France. 4. and University College, London, UK. We report the results ofthe first large-scale prospective cohort study ofthe uptake Huntington's disease (HD) is one of an increasing number of inherited neurodegenerative short-term impact of BRCAI testing on quality of life and medical decision-making. diseases caused by a CAG/Glutamine repeat expansion. The repeat is located in the first BRCAI test results were offered to 279 adult male and female members of BRCAI- exon of a ubiquitously expressed gene of unknown function and normal and expanded linked HBOC families after education and counseling sessions in a research setting. repeat ranges of 6-34 and 35-121 respectively have been reported.
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