Mutation analysis of haemophilia B in the Irish population: increased prevalence caused by founder effect

Haemophilia B generally arises as a result of unique mutations within the F9 gene and occurs with a prevalence of approximately one case per 30 000 males worldwide. The population prevalence of haemophilia B in Ireland at one per 12 500 males is particularly high. To identify the mutations responsible for haemophilia B and to define the biological basis underlying the increased prevalence in the Irish population, we performed sequence analysis of the F9 gene in 51 apparently unrelated kindred. In 18 kindred with severe or moderate haemophilia B, we identified 14 different mutations; these occurred throughout the F9 gene and included small deletions, missense, non-sense and splice-site mutations and included four novel candidate mutations. In contrast to the variety of different causative mutations with moderate or severe haemophilia B, we found three common mutations accounted for 83% (24/29) of Irish kindred with mild haemophilia B. The mutation n-6 G>A in the promoter region of F9 (which results in the characteristic haemophilia B Leyden phenotype) was found in 10 unrelated kindred. The mutation C>T 30933 in exon 8 (Ala271Val) was identified in a further 10 apparently unrelated kindred. Finally, 10430 G>A mutation (Gly60Ser) was observed in four different kindred. Haplotype analysis was performed on the index cases with the most common mutations and supported the hypothesis that the increased population prevalence of mild haemophilia B in the Irish population arose as a result of founder effect rather than an increased incidence of de-novo F9 mutations.