HemophiliaB: molecular pathogenesis and mutation analysis

HemophiliaB is an X-chromosome-linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factorIX activity (FIX:C) levels may also experience some bleeding. Genetic analysis has been undertaken for hemophiliaB since the mid-1980s, through linkage analysis to track inheritance of an affected allele, and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in >97% of patients with hemophiliaB. The risk of the development of inhibitory antibodies, which are reported in similar to 2% of patients with hemophiliaB, can be predicted, especially in patients with large deletions, and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally in patients with small insertions/deletions or splice mutations, and rarely in patients with missense mutations (p.Gln237Lys and p.Gln241His). HemophiliaB results from several different mechanisms, and those associated with hemophiliaB Leyden, ribosome readthrough of nonsense mutations and apparently silent' changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders, including hemophiliaB, are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity, and a growing range of algorithms are available to help predict pathogenicity for previously unreported variants.