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.