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Study Finds Hemophilia B-Causing Mutation in Russian Royal Remains

NEW YORK (GenomeWeb News) – In a genetic study appearing in the advance, online edition of Science today, Russian and American researchers reported that Alexei Romanov and other members of the European royal family were afflicted with a type of hemophilia called hemophilia B.

The researchers examined nuclear and mitochondrial DNA from skeletal remains found in graves near Yekaterinburg, previously shown to belong to the Russian royal family. They identified a telltale mutation affecting the splicing of a blood coagulation gene called F9 and leading to hemophilia B, also known as "Christmas disease."

Work by the same team, published online in the Proceedings of the National Academy of Sciences this past February, confirmed that the entire Romanov family was murdered during the Russian Revolution.

For the current study, the team tested DNA from the same remains to better understand the bleeding disease that plagued the family's youngest child Alexei and other European royals.

"The 'Royal disease,' a blood disorder transmitted from Queen Victoria to European Royal families, contributed to pivotal events in European history and is one of the most striking examples of X-linked recessive inheritance," co-lead author Evgeny Rogaev, a researcher affiliated with the University of Massachusetts, the Lomonosov Moscow State University, the Vavilov Institute of General Genetics, and the Research Center of Mental Health in Moscow, and co-authors explained.

The team used massively parallel sequencing to sequence several nuclear genes, including blood coagulation Factor VIII (F8) and Factor IX (F9). They also evaluated complete mitochondrial sequence data to identify each individual and keep tabs on potential contamination.

The researchers did not find missense mutations, insertions, or deletions in any of the F8 or F9 gene sequences they tested. On the other hand, they did identify a substitution upstream of one of the F9 exons.

Two members of the Romanov family carried this F9 mutation: Alexei was hemizygous for the mutation and one of his sisters, likely Anastasia, was a heterozygous carrier.

Based on their analysis, the researchers concluded that the mutation creates a premature stop codon in the F9 gene. That, in turn, suggests Alexei had a form of hemophilia called hemophilia B, caused by mutations affecting clotting factor IX.

According to the US National Library of Medicine, hemophilia B is seven times less common than hemophilia A, which is caused by mutations that decrease the activity of clotting factor VIII.

"We conclude that the Royal disease is a severe form of hemophilia B, known as 'Christmas disease,' caused by a mutation creating an abnormal splicing site in the F9 gene," the authors wrote.