F8 – Hemophilia A
With respect to hemophilia A (n=73), 39 new variants were SNVs, 27 were deletions, two were complex mutations, four were duplications and one was an insertion (see Table 1). In mild and moderate hemophilia A, all new alterations were missense variants. Table 1 gives more detailed information on variant type and effect in all variants found in the cohort.
Variants that could be classified directly as causing severe hemophilia were: deletions (n=27), duplications (n=4), insertions (n=1) and complex mutation type (n=2) causing frameshift, small and large structural changes (reported in Table 2) and variants causing nonsense effect (n=11) (reported in Table 3).
SNVs leading amino acid alterations (missense) and splice site mutations underwent in silico analysis with prediction programs, as described above. Twenty-three of 26 variants causing missense mutations (Table 4) and seven of nine splice site variants (Table 5) could be confirmed as causing hemophilia. The five variants were classified as non-disease causing or likely benign (Tables 6 and 7). In total, 73 of 78 new variants found in this cohort were found to be causative of hemophilia A. Inhibitors were diagnosed in 18 patients carrying one of these 73 new variants, all found in patients with the severe form of the disease, with the exception of one variant p.Glu409Lys found in moderate hemophilia.