The British "Royal Disease," a blood disorder transmitted from Queen Victoria to European royal families, is a striking example of X-linked recessive inheritance. Although the disease is widely recognized to be a form of the blood-clotting disorder hemophilia, its molecular basis has never been identified, and the royal disease is now extinct.

We identified the likely disease-causing mutation by applying genomic methodologies (multiplex target amplification and massively parallel sequencing) to historical specimens from the Romanov branch of the royal family. The mutation occurs in F9, a gene on the X chromosome that encodes blood coagulation Factor IX, and is predicted to alter RNA splicing and lead to production of a truncated form of Factor IX. Thus, the royal disease is the severe form of hemophilia, also known as hemophilia B or Christmas disease.

Evgeny I. Rogaev, Anastasia P. Grigorenko, Gulnaz Faskhutdinova, Ellen L. W. Kittler, Yuri K. Moliaka

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