Molecular characterization of female hemophilia A by multiplex ligation-dependent probe amplification analysis and X-chromosome inactivation study

Hemophilia A is an X-linked recessive bleeding disorder caused by mutations in the F8 gene. Hemophilia A typically occurs in male individuals, but female patients with hemophilia A have rarely been reported. Here we describe molecular characteristics of three unrelated female patients with severe hemophilia A of Korean descent. Patient 1 was a 5-year-old girl and was found to be compound heterozygous for intron 22 inversion inherited from her father with hemophilia A and a large deletion mutation from her mother. The large deletion detected by multiplex ligation-dependent probe amplification involved the whole F8 gene. Patient 2 was a 30-year-old woman and was heterozygous for small duplication mutation in exon 14 (c.3275dupA; p.Asn1092LysfsX26). Patient 3 was a 16-year-old girl and was heterozygous for intron 22 inversion. All three patients showed nonrandom X-chromosome inactivation status. The results underscore the need for a meticulous search for another mutation in the maternally derived X-chromosome such as large-dosage mutations.