The high frequency of the -6G-->A factor IX promoter mutation is the result both of a founder effect and recurrent mutation at a CpG dinucleotide.

Abstract

We report a new Liverpool family with a mild haemophilia B Leyden phenotype caused by a -6G-->A mutation in a CpG dinucleotide in the promoter of the clotting factor IX gene. This mutation had previously been identified in three other U.K. pedigrees and six others worldwide. To investigate whether these mutations were of independent origin, the haplotype was determined for eight polymorphic loci, within or immediately adjacent to the factor IX gene, for nine of the 10 existing patients. Six probands had identical haplotypes, including all four U.K. probands, suggesting that they arose from a common founder. The other three probands differed in haplotype from the common haplotype, and from each other, suggesting that they were independent mutations at this CpG dinucleotide.