Moderate hemophilia B Leyden: identification by polymerase chain reaction, sequencing, and oligomer restriction

Hemophilia B Leyden is a rare form of congenital factor IX deficiency which is characterized by severe factor IX deficiency at birth, which ameliorates after puberty. It is caused by mutations in the factor IX gene promoter region and the postpubertal amelioration is thought to be mediated by the action of testosterone on an androgen response element located in the promoter region. Three kindreds have been previously reported with a milder form of hemophilia B Leyden, associated with a guanine to adenine transition at nucleotide position -6 of the promoter region. We now report a fourth kindred with this mutation. The proband was a newborn with a factor IX level of 2.5%, his 12-year-old half-brother had a level of 28%, and his mother's 56-year-old maternal cousin had a level of 60%. A G to A transition at nucleotide -6 of the promoter region was demonstrated by cloning and sequencing polymerase chain reaction products from the half brother, and the mother was demonstrated to be a carrier. The mutation eliminates a TaqI restriction endonuclease site normally present in the wild type promoter, and the mother's cousin was demonstrated to carry the mutation by the absence of digestion with TaqI. The identification of hemophilia B Leyden with this specific mutation has practical importance to the clinical management because of its unique natural history and significantly better prognosis than classical hemophilia B.