An Ancestral Ashkenazi Haplotype at the HMPS/CRAC1 Locus on 15q13–q14 Is Associated with Hereditary Mixed Polyposis Syndrome

The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16–q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorr...

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Bibliographic Details
Published in:American journal of human genetics 2003-05, Vol.72 (5), p.1261-1267
Main Authors: Jaeger, E.E.M., Woodford-Richens, K.L., Lockett, M., Rowan, A.J., Sawyer, E.J., Heinimann, K., Rozen, P., Murday, V.A., Whitelaw, S.C., Ginsberg, A., Atkin, W.S., Lynch, H.T., Southey, M.C., Debinski, H., Eng, C., Bodmer, W.F., Talbot, I.C., Hodgson, S.V., Thomas, H.J.W., Tomlinson, I.P.M.
Format: Article
Language:English
Subjects:
Adenomatous Polyposis Coli - genetics
Biological and medical sciences
Chromosome Mapping
Chromosomes, Human, Pair 15 - genetics
Chromosomes, Human, Pair 6 - genetics
Female
Gastroenterology. Liver. Pancreas. Abdomen
Genetic Linkage
Genetic Predisposition to Disease
Genetic Testing
Haplotypes - genetics
Humans
Jews - genetics
Lod Score
Male
Medical sciences
Pedigree
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
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Summary:The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16–q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13–q14.
ISSN:0002-9297
1537-6605
DOI:10.1086/375144