HEMOPHILIA-B IN FEMALE TWINS CAUSED BY A POINT MUTATION IN ONE FACTOR-IX GENE AND NONRANDOM INACTIVATION PATTERNS OF THE X-CHROMOSOMES

Haemophilia B is a X-linked recessive bleeding disorder with an incide nce of 1:25,000-30,000 male birth. Usually female carriers are clinica lly normal. Phenotypic expression of the disease in female carriers is extremely rare. We describe cytogenetically inconspicuous female iden tical twins both with factor IX levels below 2%, prolonged bleeding af ter veni-puncture as well as haematomas after intramuscular injections . The father, suffering from a severe haemophilia B, is deceased. By s equencing one point mutation was characterized in heterozygote conditi on in the factor IX gene of the probands at nt 17678. This mutation le ads to the substitution cystein 88 to tyrosine in the growth factor do main of the factor IX. Investigation of the X-chromosomal inactivation by comparison of methylation patterns of genomic DNA at locus DXS255 after digestion with Pst I and Pst I +Hha I and hybridisation with the probe M27 beta indicated a nonrandom pattern of X-chromosomal inactiv ation in the twins. In both girls, only the paternal X-chromosome was the active one leading to the phenotypic expression of haemophilia in the female carriers.