Haemophilia B mutations in Sweden: a population-based study of mutational heterogeneity

The present series comprises all families (n = 77) with haemophilia B in Sw eden and may be considered to be representative for the purposes of a popul ation-based study of mutational heterogeneity, The 77 families (38 severe, 10 moderate, 29 mild) had 51 different mutations in total. Thirteen familie s had total, partial or small deletions, two had mutations in the promoter, eight families had splice site mutations, 14 had nonsense and the remainin g 41 had missense mutations. Ten of the mutations, all C -->T or G -->A, re curred in 1-6 other families. Using haplotype analysis of seven polymorphis ms in the factor IX (FIX) gene, we found that the 77 families carried 65 un ique, independent mutations, Of the 48 families with severe or moderate hae mophilia, 23 (48%) had a sporadic case of haemophilia compared with 31 fami lies out of 78 (40%) in the whole series, Five of those 23 sporadic cases c arried de novo mutations, 11 out of 23 of the mothers were proven carriers and, in the remaining seven families, it was not possible to determine carr iership. Eleven of the 48 patients (23%) with severe haemophilia B develope d inhibitors and all of them had deletions or nonsense mutations. Thus, 11 out of 37 (30%) patients with severe haemophilia B as a result of deletion/ nonsense mutations developed inhibitors compared with 0 out of 11 patients with missense mutations. The ratio of male to female mutation rates was 5.3 and the overall mutation rate was 5.4 x 10(-6) per gamete per generation.