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We have identified 14 mutations of the factor VIII (F8) gene from a panel of 107 patients with hemophilia A and have characterized these gene defects by restriction analysis, oligonucleotide hybridization, cloning and DNA sequencing. Recurrent point mutations that involve CG to TG transitions were identified in exon 18, exon 22 and exon 24, and a single CG to TG transition was identified in exon 23. In addition, a Taq I site alteration in intron 4 of the F8 gene was identified in a patient with mild hemophilia. Cloning and sequencing of this region suggests that a change in this Taq I site may create a new splice donor site. These data suggest that CG to TG transition is a prominent mechanism of mutation in hemophilia A. We estimate that the mutation rate of CG to TG in the F8 gene is at least 100 times greater than the average mutation rate per nucleotide. Six different deletions were also characterized. In one family, the deletion involved exon 26. However, the deletion endpoints in the male proband were different from those in his carrier mother, suggesting either gonadal mosaicism or a second deletion event in maternal meiosis.

Of the 14 mutations, 6 occurred de novo within 2 generations; 4 in males and 2 in females. In these de novo mutations paternal age at conception was 35 (range = 32-38) and maternal age was 24 and 27. The ability to discover a sizable number of mutations in the F8 gene producing hemophilia A enables us to determine the frequency and nature of de novo mutations in man.

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