Molecular mechanisms underlying hemophilia A phenotype in seven females

J Thromb Haemost. 2009 Jun;7(6):976-82. doi: 10.1111/j.1538-7836.2009.03346.x. Epub 2009 Mar 19.


Background: Hemophilia A (HA) in females is a rare observation. Here we describe various genetic mechanisms that result in phenotypic expression of HA in seven females.

Methods: The F8 gene was examined in all patients and relatives by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed for large deletion screening. X chromosome inactivation was studied by PCR analysis of a polymorphic CAG repeat in the first exon of the human androgen receptor (HUMARA) gene.

Results: In two females sequencing of the F8 gene revealed homozygous missense mutations (Arg593Cys and Tyr1680Phe) as a consequence of consanguineous marriage. The third case was due to compound heterozygosity comprising the missense mutation Leu412Phe inherited from the carrier mother, together with a de novo large deletion spanning exon 9-22, probably originating from the germ cells of the healthy father. Three further cases shared a common mechanism representing heterozygous mutations in the F8 gene (Arg1781His, Arg327His, small deletion in exon 10) combined with non-random inactivation of the X chromosome. The final case describes a coincidental inheritance of HA and Coffin-Lowry syndrome in the same family. The HA phenotype results from a heterozygous small deletion affecting the F8 gene (c.6872 del CT leading to Thr2272fs) and a complete inactivation of the maternal X chromosome, which segregates with Coffin-Lowry syndrome in the two brothers of the proposita.

Conclusions: In conclusion, molecular genetic analysis represents an essentially valuable tool in elucidating the nature of the molecular mechanisms underlying the HA phenotype in females.

MeSH terms

  • Adult
  • Child, Preschool
  • Female
  • Hemophilia A / genetics*
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction
  • X Chromosome Inactivation