Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype

Haemophilia. 2005 Mar;11(2):133-41. doi: 10.1111/j.1365-2516.2005.01069.x.


We report the results of genetic analysis on a series of 51 patients attending this Haemophilia Comprehensive Care Centre. The most common cause of severe haemophilia A--the factor VIII intron 22 inversion was detected in eight families and the factor VIII intron 1 inversion in three families. Mutation analysis was carried out on the remaining patients by nucleotide sequencing of genomic DNA after screening with conformation-sensitive gel electrophoresis (CSGE) or denaturing high-performance liquid chromatography (dHPLC). A total of 27 different FVIII non-inversion mutations were detected. Severe haemophilia was associated with 12 null mutations (six nonsense, six frameshift) and four missense mutations. A further 11 different missense mutations were associated with moderate or mild disease. To our knowledge, six null mutations [1950del 4(tttg), 3270-75insA, 4416del 10, 6735-38delA, W1029X, Y1792X] and four missense mutations (E1682K, M1947V, P2048L, P2143L) have not been previously published. Each novel missense mutation occurred at a highly conserved residue, no other candidate mutation was detected on screening the entire coding region of the FVIII gene and they were not detected in a screen of individuals without haemophilia A. The genotype-phenotype correlations of the FVIII mutations detected will be discussed.

MeSH terms

  • Base Sequence
  • Codon, Nonsense / genetics
  • DNA / genetics
  • DNA Mutational Analysis / methods
  • Factor VIII / antagonists & inhibitors
  • Factor VIII / genetics
  • Frameshift Mutation / genetics
  • Genotype
  • Hemophilia A / genetics*
  • Humans
  • Inteins / genetics
  • Male
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Phenotype


  • Codon, Nonsense
  • Factor VIII
  • DNA