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Analysis of haemophilia B database and strategies for identification of common point mutations in the factor IX gene

Summary.  Haemophilia B is an X‐linked recessively inherited bleeding disorder caused by heterogeneous mutations spanning the entire factor IX gene. As spontaneous germ‐line mutations are known to occur mostly at CpG dinucleotides in the FIX gene, control of the disease would require continuous carrier detection and mutation screening. Identification of point mutations, the most common type of mutation in FIX gene, is more challenging compared with deletion and insertion mutations. We examined the haemophilia B database to identify specific nucleotides in the FIX gene that are mutated in relatively large number of patients and the variability (if any) in the mutational hotspots at CpG dinucleotides. It was found that while mutations responsible to account for all 2348 haemophilia B patients covered 20% of the FIX cDNA, only 1% of the cDNA involving mostly CpG dinucleotides accounted for mutation in 42.41% of the patient pool. Thus, only 27 nucleotides need to be investigated to identify the common point mutations, among which 15 are predicted to undergo change in restriction sites on mutation. It is interesting to note that seven nucleotides occurring in CpG dinucleotides do not have any reported mutation despite each of those being predicted to harbour mutation as a result of transition and having mutations recorded in the database for the neighbouring nucleotides. Strikingly large number of mutation in codon 296 causing T to M change in catalytic domain originally proposed to be the result of the founder effect also contains largest number of haplotype suggesting recurrence of de novo mutation.