Summary
Inversion involving intron 22 is the commonest type of mutation causing severe hemophilia
A (HA). We investigated 15 families with isolated cases and 5 families with two or
three brothers as the only affected members with hemophilia A, in order to determine
the carrier status of the mothers, the origin of the mutation and the presence of
germinal mosaicism. Our results show that all mothers tested were carriers of the
inversion. In addition, three families whose unique hemophilic member was not available
for analysis, were screened for the inversion. In one of these last families, the
mother was diagnosed as a carrier and her sister and her niece as non-carriers. DNA
haplotype analysis in 8 families with grandparents available for study demonstrated
that the inversion originated almost exclusively in male germ cells. These findings
have important relevance for genetic counselling in families with an isolated case
or to exclude germinal mosaicism. Inversion analysis should constitute the first step
in molecular diagnosis of severe hemophilia A.
