Absence of correlation between X chromosome inactivation pattern and plasma concentration of factor VIII and factor IX in carriers of haemophilia A and B

Haemophilia A and B are X-linked disorders which are due to a reduced activ ity of coagulation factor VIII or IX, respectively. Female carriers have a wide range of plasma concentration of factor VIII or factor IX, and may in rare cases have an affected phenotype. In order to investigate if this vari ation is related to X chromosome inactivation, we determined the X inactiva tion pattern in 31 haemophilia A and 15 haemophilia B carriers, using a PCR in the androgen receptor locus in blood DNA. Seven of the haemophilia A ca rriers and none of the haemophilia B carriers had a skewed pattern (greater than or equal to 80:20). One of the skewed haemophilia A carriers had a lo w plasma concentration of factor VIII (0.15 U/ml), but the remaining 6 carr iers did not differ in factor VIII concentration from that of carriers with a random X inactivation pattern. One carrier with a high factor VIII conce ntration (2.0 U/ml) did not have a skewed pattern. Similarly, for the haemo philia B carriers, then was no tendency to a more skewed X inactivation pat tern in the carriers with low or high factor IX concentrations. In addition , we analysed a female with haemophilia B who was heterozygous for the muta tion R180W in the factor IX gene. She had a random X chromosome inactivatio n pattern. We conclude that the wide range in plasma concentration of facto r VIII and factor TX in haemophilia A and B carriers cannot in general be e xplained by the X chromosome inactivation pattern in peripheral blood cells .