Direct detection of a common inversion mutation in the genetic diagnosis of
severe hemophilia A [see comments]
S Windsor, SA Taylor and D Lillicrap
Department of Pathology, Queen's University, Kingston, Ontario, Canada.
Two recent reports suggest that approximately 50% of the cases of severe
hemophilia A (factor VIII:C < 0.01 U/mL) may be caused by a gross
rearrangement of the factor VIII gene. The mutation involves genomic
sequence from exon 1 to within intron 22 of the gene in an inversion event.
This rearrangement can be detected on a Southern blot using a probe that is
complementary to sequence from within intron 22. In this report, we
describe the analysis of 71 severe hemophilia A patients for the presence
of this mutation. Thirty-two of the patients (45%) showed evidence of the
rearrangement, a figure that confirms the initial reports on 28 patients.
Five different patterns of rearrangement have been noted, although two of
these patterns (pattern 1 [70%] and pattern 2 [16%]) account for the
majority of cases. The other patterns of rearrangement appear to be
confined to individual families and may represent the result of additional
sequence variation within the region of the genome to which the proximal 22
exons of factor VIII are translocated. Analysis of this patient population
for the factor VIII inversion mutation has been extremely useful in a
molecular diagnostic sense. In 23 of the cases studied (72%), the affected
individual was the only documented hemophiliac in the family and, thus,
previous linkage analysis had been limited to the provision of exclusion
testing only. In conclusion, it appears that testing for the factor VIII
inversion mutation will be positive in approximately 45% of severe
hemophiliacs and as such should constitute the initial stage in the genetic
testing protocol for these patients' families.
Volume 84,
Issue 7,
pp. 2202-2205,
10/01/1994
Copyright © 1994 by The American Society of Hematology
