Analysis of factor VIII gene intron 1 inversion in Argentinian families with severe haemophilia A and a review of the literature.

Besides intron 22 factor VIII gene inversion (Inv22), intron 1 inversion (Inv1) has recently been reported as a further recurrent mutation that causes approximately 5% of severe haemophilia A (HA) cases. We analysed the presence of the Inv1 in a group of 64 severe HA-affected families from Argentina, and found only one positive case. This Inv1 patient has not developed a factor VIII inhibitor, and the screening for small mutations in the coding sequences of the factor VIII gene did not detect any additional defect in this case. The Inv1 genotyping was further applied to analyse the haemophilia carrier status of the proband's sister. In addition, we studied the accuracy of the current polymerase chain reaction-based method to investigate the Inv1, and confirmed the absence of amplimer length polymorphisms associated to the Inv1-specific polymerase chain reaction amplifications in 101 X-chromosome haplotypes from unrelated Argentinian healthy males. In order to discuss Inv1 mutation frequency in severe HA and the risk of inhibitor formation, a review of the literature was included. Our data highlight the importance of analysis of the Inv1 in Inv22-negative severe HA cases. This will benefit both genetic counselling and the study of the relationship between genotype and inhibitor development.