SEVERE HEMOPHILIA-A IN A FEMALE RESULTING FROM 2 DE-NOVO FACTOR-VIII MUTATIONS

A 2-year-old girl is described with severe haemophilia A (factor VIII: C <0.01 units/ml). Both of her parents were phenotypically normal. Cyt ogenetic analysis on the proband demonstrated an interstitial X chromo some deletion encompassing Xq26-q28. Molecular studies with several po lymorphic markers close to and within the factor Vm gene showed that t he proband had inherited only the paternal factor Vm gene, indicating that the X chromosome deletion had occurred de novo in the maternal ge rm line. Further study of the factor VIII gene inherited by the proban d from her father showed the presence of a de novo gene inversion muta tion (a type 1, distal pattern inversion). Neither parent showed any e vidence of the factor VIII inversion in their somatic DNA. The severe haemophilia A documented in this girl is therefore the result of two d e novo mutations affecting the factor Vm gene, a maternally derived X chromosome deletion and a paternal factor VIII inversion mutation.