Objective:
Hemophilia A and B are X-linked bleeding disorders caused by the deficiency of clotting factor VIII or IX, respectively. Mutations in the F8 gene can result in hemophilia A while mutations in the F9 gene can lead to hemophilia B. The objective of this analysis was to evaluate the F8 and F9 genotypes of subjects screened for enrollment in the phase III clinical trials of rFVIIIFc in hemophilia A (A-LONG) and of rFIXFc in hemophilia B (B-LONG).
Methods:
The F8 and F9 genotypes of 170 subjects with severe hemophilia A and 114 subjects with severe hemophilia B, respectively, were compared with several genotype databases (HAMSTeRS, [Hemophilia A Mutation, Structure, Test and Resource Site], CHAMP [CDC Hemophilia A Mutation Project], and King’s College London Hemophilia B database), as well as with the NCBI human F8 and F9 sequences.
Summary:
Among 170 subjects with hemophilia A, inversions in intron 22 (Int22inv) were identified in 36%, nucleotide substitutions in 39%, frameshift mutations in 21%, Int1inv in 3%, and an in-frame duplication in 1 subject. Previously unreported mutations (frameshift, missense, nonsense, and splice site changes) were found in 24 subjects, with 2 unrelated subjects having the same mutation, resulting in 23 novel mutations being identified. Among 114 subjects with hemophilia B, the majority (86%) had some form of substitution mutation (missense, nonsense, splice-site change), consistent with previous reports. Thirteen previously unreported mutations were identified, including 10 substitutions (7 missense, 2 nonsense and 1 splice-site change), 1 deletion, and 2 insertions.
Conclusions:
In this analysis, 23 previously unreported mutations in the F8 gene of subjects with severe hemophilia A and 13 in the F9 gene of subjects with severe hemophilia B were identified. Identifying mutations allows for prenatal diagnosis and identification of carrier status. These results will lead to further enhancement of databases for hemophilia A and B mutations and may assist in clarifying the relationship between genotype, phenotype, and pathophysiology in individuals with hemophilia.