F8 gene inversion and duplication cause no obvious hemophilia A phenotype.

Hemophilia A (HA, OMIM#306700) is an X-linked recessive bleeding disorder caused by the defects in the gene, which encodes coagulation factor VIII (FVIII). Intron 22 inversion (Inv22) is found in about 45% of patients with severe hemophilia A. Here, we reported a male without obvious hemophilia A phenotype but bearing an inherited segmental variant duplication encompassing as well as Inv22. The duplication was approximately 0.16 Mb and involved from exon 1 to intron 22 of . This partial duplication and Inv22 in was first found in the abortion tissue of his older sister with recurrent miscarriage. The genetic testing of his family revealed that his phenotypically normal older sister and mother also had this heterozygous Inv22 and a 0.16 Mb partial duplication of , while his father was genotypically normal. The integrity of the gene transcript was verified by sequencing of the adjacent exons at the inversion breakpoint, which explained why this male had no phenotype for hemophilia A. Interestingly, although he had no significant hemophilia A phenotype, the expression of in his mother, sister, and the male subject was only about half of that in his father and normal population. Our report broadens the mutation spectrum of inversion and duplication and its pathogenicity in hemophilia A.