LINKAGE OF COMBINED FACTOR-V AND FACTOR-VII DEFICIENCY TO CHROMOSOME 18Q BY HOMOZYGOSITY MAPPING

Combined Factors V and VIII deficiency is an autosomal recessive bleed ing disorder identified in at least 58 families comprising a number of different ethnic groups. Affected patients present with a moderate bl eeding tendency and have Factor V and Factor VIII levels in the range of 5-30% of normal. The highest frequency of the mutant gene is found in Jews of Sephardic and Middle Eastern origin living in Israel with a n estimated disease frequency of 1:100,000. We sought to identify the gene responsible for combined Factors V and VIII deficiency using a po sitional cloning approach. Of 14 affected individuals from 8 unrelated Jewish families, 12 were the offspring of first-cousin marriages. Aft er a genome-wide search using 241 highly polymorphic short tandem repe at (STR) markers, 13 of the 14 affected patients were homozygous for t wo closely linked 18q markers. Patients and all available family membe rs were genotyped for 11 additional STRs spanning similar to 11 cM on the long arm of chromosome 18. Multipoint linkage analysis yielded a m aximal log of the odds (LOD) score of 13.22. Haplotype analysis identi fied a number of recombinant individuals and established a minimum can didate interval of 2.5 cM for the gene responsible for combined Factor s V and VIII deficiency. The product of this locus is likely to operat e at a common step in the biosynthetic pathway for these two functiona lly and structurally homologous coagulation proteins. Identification o f this gene should provide new insight into the biology of Factor V an d Factor VIII production.