Last update: 05/06/2006
Background to disease
OMIM # 306700
Haemophilia A is a recessive, X-linked bleeding disorder affecting approximately 1/5000 males due to a deficiency of blood coagulation Factor VIII. The severity of the condition varies from severe (<1% normal clotting activity), moderate (2-5%) to mild (5-30%). Further complications may arise due to the presence of inhibitors (antibodies) to replacement factor VIII. The gene, at Xq28, is 186kb long and has 26 exons, which encode a 9kb message.
Clinical diagnosis can be made based on factor VIII levels in the blood. Carrier females can be detected to a certain extent by blood factor VIII levels.
Several polymorphisms have been discovered that are associated with the factor VIII gene and can therefore be used in haemophilia A diagnosis.
In 50% of severe haemophilia A cases an inversion in intron 22 of FVIII (‘flip tip’) is the causative mutation. Intron 22 is large and contains a CpG island which acts as a bi-directional promoter for two ubiquitously expressed genes referred to as factor VIII- associated genes A and B. Gene A is transcribed in the opposite direction to factor VIII and is completely nested within intron 22. Two further copies of this gene lie ~500kb upstream of the factor VIII gene and are in the opposite orientation to the intron 22 copy.
The inversion mutation is produced as a result of homologous recombination between the intron 22 copy of gene A and one of the upstream copies. A crossover between these two identical regions results in an inversion of the intervening sequence. Recombination with the most distal A gene seems to occur more frequently than with the proximal copy. This mutation can be detected by Southern analysis (not currently offered in this laboratory).
Laboratory Analysis
Contact scientist: David Cockburn
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Linked markers |
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