Origin of mutation in sporadic cases of haemophilia A

The aim of this study was to define the origin of mutation in sporadic cases of severe haemophilia A. The series was composed of 31 families with sporadic severe haemophilia A in the geographical catchment area of the Malmo haemophilia centre. The mutation was characterized in 29/31 families: inversion type 1 (n = 11), inversion type 2 (n = 3), other inversion (n= 1), small or partial deletion (n = 6), insertion (n = 2), non-sense mutation (n = 4) and mis-sense mutation (n = 2). Of 29 probands, eight carried a de novo mutation, whereas the proband's mother was found to carry the mutation in 21/29 families. Of the 21 carrier mothers, 16 had de novo mutations (i.e. the proband's maternal grandfather and grandmother were non-carriers). Owing to the lack of samples from the grandparents, origin could not be determined in the remaining five families. Polymorphisms of the FVIII gene were used to determine whether the de novo mutation of the carrier mother was of paternal or maternal origin. In 15/16 cases the mutation was of paternal origin and in 1/16 cases of maternal origin. In the series as a whole, mutation frequency was 6-fold higher in males than in females, but no differences in the ratio of sex-specific mutations rates was found among different types of mutation.