Genotype

Even though much progress was recently done to unravel the molecular lesions underlying RBDs (Figure 3) -2-,3-,

RBDs are usually due to mutations in the genes that encode the corresponding coagulation factors. Exceptions are the combined deficiency of FV and FVIII, characterized by defects in genes encoding proteins involved in the intracellular transport of these factors -4-,5 and the combined deficiency of vitamin K-dependent FII, FVII, FIX, and FX, characterized by defects in the genes encoding enzymes involved in posttranslational modifications of these factors and in vitamin K metabolism -6-.

In contrast to haemophilia A, where inversion events involving intron 22 or intron 1 of the FVIII gene are responsible for approximately half of the all cases; RBDs are generally caused by mutations unique to each kindred -2-. In approximately 10% to 20% of patients, no putative mutation is found.

These cases may be due to defects in non-coding regions or in genes coding for regulators of intracellular transport and posttranslational modifications of coagulation factors.
To date knowledge of the underlying mutation(s) in the affected gene has not been widely exploited to allow reproductive choices to be made within kindred by genetic counselling and prenatal diagnosis