Trisomy X conferring moderate hemophilia A by extremely skewed X-chromosome inactivation

Hemophilia carriers occasionally present with bleeding tendency due to skewed inactivation of normal F8 carrying X chromosome.

Can extreme skewing of X-chromosome inactivation (XCI) with trisomy X cause low factor (F) VIII activity and bleeding in a hemophilia carrier?.

A young female with low FVIII activity (2 IU/dL), who presented with history of frequent bleeding and F8 variant, NP_000123.1:p.(Arg1800His), was identified. The mother was also confirmed genetically as hemophilia carrier. Karyotype was 47, XXX, multiplex ligation-dependent probe amplification for aneuploidy in the family identified trisomy X only in the index case. Digital polymerase chain reaction using leucocytes, urine, and oral mucosa identified one maternal F8 variant carrying and 2 wild-type F8 carrying X chromosomes, but it detected no somatic mosaicisms. Methylation-sensitive-HpaII-polymerase chain reaction assay showed predominantly activated maternal and 2 fully inactivated paternal X chromosomes. The XCI patterns using tissues of different developmental origins showed extremely skewed XCI.

Extreme skewing of XCI can occur even in hemophilia carriers with trisomy X, conferring frequent bleeding and low FVIII activity.