Severe hemophilia A due to a 1.3 kb factor VIII gene deletion including exon 24: homologous recombination between 41 bp within an Alu repeat sequence in introns 23 and 24

J Thromb Haemost. 2004 Nov;2(11):1941-5. doi: 10.1111/j.1538-7836.2004.00963.x.


Partial or complete factor (F)VIII gene deletions are found in about 5% of families with severe hemophilia A. Relatively few deletions have been well characterized and, of these, recombination occurred between either common repeat elements or non-homologous sequences. In evaluating a family with severe hemophilia A, an exon 24 deletion was suspected when no fragment was obtained on attempted PCR amplifications. A combination of the 5' primer of exon 23 and the 3' primer of exon 25 fragments was used with prolonged extension times to amplify a normal 2.9 kb fragment that included exons 23 through 25; the patient's amplified product was 1.6 kb indicating a 1.3 kb deletion. A mixture of normal and patient DNA showed both sized fragments as did that from an obligate carrier. Carrier detection was applied to two women at risk; one was and one was not a carrier. Sequencing the proband's 1.6 kb fragment revealed that a 1328 bp deletion occurred between homologous sequences of 287 and 285 bp in introns 23 and 24, respectively; these share 85% identity. Blast nucleotide search revealed that these represent Alu elements. Comparison with an alignment of each of the two homologous sequences further localized recombination to a 41-bp segment. However, a simple recombination event would not account for the proband's sequence. The most likely explanation is that the homologous recombination was accompanied by incomplete mismatch repair.

Publication types

  • Case Reports

MeSH terms

  • Alu Elements
  • Base Sequence
  • DNA Mutational Analysis
  • Exons
  • Factor VIII / genetics*
  • Family Health
  • Female
  • Gene Deletion*
  • Genetic Carrier Screening
  • Hemophilia A / etiology
  • Hemophilia A / genetics*
  • Humans
  • Introns / genetics
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Recombination, Genetic


  • Factor VIII