Frequency and Inhibitor Risk of the Intron-1-Inversion Mutation in the German Hemophilia Population
J. Schröder, J. Graw, H.-H. Brackmann, B. Kellner, S. Löffler, W. Schramm, R. Schwaab, C. Müller-Reible and J. Oldenburg
Background
The Intron-1-Inversion represents the most recently discovered mutation mecha- nism of the factor VIII (FVIII) gene (Bagnall et al. 2002). The mutation is caused by an intrachromosomal recombination of two repeats, located within intron 1 and the telomeric end of the FVIII gene. It can be easily analyzed by a PCR shown in Figure 1. Several groups reported an intron 1 inversion prevalence of 4-5% in severely affected hemophilia A patients. However, these studies were based on small patient numbers. Moreover, because of the low frequency of the intron 1 inversion, no data on inhibitor risk were available. The reported studies suggest a low inhibi- tor prevalence of 10-15%. Based on a large scale mutation profiling in the German hemophilia population this study aims to provide more exact information on fre- quency and inhibitor risk of this specific FVIII gene mutation.
Results and Discussion
Analyzing 794 index patients from German families with severe hemophilia A we found 19 patients with an inversion resulting in a prevalence of 2.4%. The other mutation types distributed as follows: intron-22-inversion in 363 (45.7%) patients,
wt wt inv wt inv inv wt wt wt het
wt wt inv wt inv inv wt wt wt het
b b
Fig. 1a, b. Fragment Inth1-1: Lanes 1,2,4,7,8,9 wildtype (wt); 3,5 Intron-1-Inversion (inv); 6:
heterozygous Intron-1-Inversion (inv het); b) Fragment Inth1-2: Lanes 1,2,4,7,8,9 wildtype 3,5 Intron-1-Inversion; 6 heterozygous Intron-1-Inversion
I. Scharrer/W. Schramm (Ed.)
34thHemophilia Symposium Hamburg 2003
” Springer Medizin Verlag Heidelberg 2005
big deletions/insertions in 31 (3.9%) patients, small deletions/insertions in 118 (14.9%) patients, missense- and stop mutations in 211 (26.6%) patients and splice site mutations in 20 (2.5%) patients. No mutation could be detected in 32 (4.0%) of the severely affected hemophilia A patients. 6 (31.6%) of the patients with an intron 1 inversion developed an inhibitor against factor-VIII-protein, including 3 patients with a low titer and 2 patients with a high titer inhibitor. In one patient the inhibi- tor titer was not known.
Conclusion
Compared to published data, our study revealed a significantly lower frequency of the intron 1 inversion mutation (2.4% vs 4-5%). The inhibitor prevalence of 30%
clearly indicates a high risk for inhibitor formation which agrees with other null mutations.
References
1. Bagnall RD, Waseem N, Green PM, Giannelli F (2002) Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 99(1):168-174 2. Riccardi F, Tagliaferri A, Manotti C, Pattacini C, Neri TM. (2002) Intron factor VIII gene
inversion in a population of Italian hemophilia A patients. Blood 100(9): 3432-3432 154 J. Schröder et al.
5,0%
3,2%
5,0%
3,8%
4,3%
4,8%
0,0%
2,4%
