Analysis of intron 22 inversions of the factor VIII gene in severe
hemophilia A: implications for genetic counseling
PV Jenkins, PW Collins, E Goldman, A McCraw, A Riddell, CA Lee and KJ Pasi
Katharine Dormandy Haemophilia Centre, Royal Free Hospital and School of
Medicine, London, UK.
Intrachromosomal recombinations involving F8A, in intron 22 of the factor
VIII gene, and one of two homologous regions 500 kb 5' of the factor VIII
gene result in large inversions of DNA at the tip of the X chromosome. The
gene is disrupted, causing severe hemophilia A. Two inversions are
possible, distal and proximal, depending on which homologous region is
involved in the recombination event. A simple Southern blotting technique
was used to identify patients and carriers of these inversions. In a group
of 85 severe hemophilia A patients, 47% had an inversion, of which 80% were
of the distal type. There was no association with restriction fragment
length polymorphism (RFLP) haplotypes. The technique has identified a
definitive genetic marker in families previously uninformative on RFLP
analysis and provided valuable information for genetic counselling
information may now be provided for carriers without the need to study
intervening family members and the diagnosis of severe hemophilia A made in
families with only a nonspecific history of bleeding. Analysis of intron 22
inversion should now be the first-line test for carrier diagnosis and
genetic counselling for severe hemophilia A and may be particularly useful
when there is no affected male family member or when intervening family
members are unavailable for testing.
Volume 84,
Issue 7,
pp. 2197-2201,
10/01/1994
Copyright © 1994 by The American Society of Hematology
