4 research outputs found
VWFâGly2752Ser, a novel nonâcysteine substitution variant in the CK domain, exhibits severe secretory impairment by hampering Câterminal dimer formation
Aberrant X chromosomal rearrangement through multiâstep template switching during sister chromatid formation in a patient with severe hemophilia A
Abstract Background Hemophilia A (HA) is an Xâlinked recessive bleeding disorder caused by pathogenic variants of the coagulation factor VIII gene (F8). Half of the patients with severe HA have a recurrent inversion in the X chromosome, that is, F8 intron 22 or intron 1 inversion. Here, we characterized an abnormal F8 due to atypical complex X chromosome rearrangements in a Japanese patient with severe HA. Methods Recurrent F8 inversions were tested with inverse shiftingâPCR. The genomic structure was investigated using PCRâbased direct sequencing or quantitative PCR. Results The proband's X chromosome had a 119.5Â kb insertion, a reverse duplex of an extragenic sequence on the F8 telomere region into the F8 intron 1 with two breakpoints. The telomeric breakpoint was a joining from the F8 intron 1 to the inverted FUNDC2 via a twoâbase microhomology, and the centromeric breakpoint was a recombination between F8 intron 1 homologous sequences. The rearrangement mechanism was suggested as a multiâstep rearrangement with template switching such as fork stalling and template switching (FoSTeS)/microhomologyâmediated breakâinduced replication (MMBIR) and/or homologous sequenceâassociated recombination during a sister chromatid formation. Conclusion We identified the aberrant X chromosome with a split F8 due to a multiâstep rearrangement in a patient with severe HA