Hemophilia A families with the same mutation are often related: a survey of the Swedish population

Aim: To study if families with hemophilia A in Sweden carrying the same mutation are identical by descent (IBD) or the result of independent mutations (RM).

Study group: A total of 284 presumed unrelated and unselected Swedish families with hemophilia A comprising all clinical severities. Control group of 254 healthy individuals.

Methods: Haplotyping was performed using 90 SNP markers (18 within the F8 gene) and 5 microsatellite markers. The frequencies of shared haplotypes were determined in the control group and the ages of the shared haplotypes determined using the program ESTIAGE.

Results: Analysis of the mutations gave the following results: inversions in introns 1 or 22 were detected in 71 cases, large deletions in 5, small deletions/insertions in 4, and substitutions in 204 patients. For substitutions, a total of 107 mutations occurred in a single individual only, whereas the remaining 35 mutations occurred in 2 or more individuals; 20 mutations occurred in 2 individuals, 9 mutations occurred in 3 individuals, m4 mutations occurred in 4 individuals, and 2 mutations occurred in 7 individuals each, i.e., 97 mutations out of 204 (47%) were either IBD or recurrent mutation. Haplotyping and comparisons with the control group classified 51 of the 97 mutations as IBD. The phenotypes of the 51 individuals were mild (31), moderate (5), and severe (8), and the corresponding mutations had age estimates varying between 150 and 700 years. Inhibitors occurred in both RM and IBD families. One IBD family with mild hemophilia (2105 Tyr>Cys) had 3 members who developed inhibitors.

Conclusion: Many families with hemophilia A, in particular those with milder forms, carrying the same mutation are IBD, i.e., revision of ‘‘hot-spots’’ for mutation is needed. Few ‘‘clusters of inhibitors’’ were found.