Open AccessAberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A
Author(s) -
Tokoro Mahiru,
Tamura Shogo,
Suzuki Nobuaki,
Kakihara Misaki,
Hattori Yuna,
Odaira Koya,
Suzuki Sachiko,
Takagi Akira,
Katsumi Akira,
Hayakawa Fumihiko,
Okamoto Shuichi,
Suzuki Atsuo,
Kanematsu Takeshi,
Matsushita Tadashi,
Kojima Tetsuhito
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1390
Subject(s) - breakpoint , genetics , chromosomal inversion , biology , non allelic homologous recombination , gene rearrangement , chromosomal rearrangement , intron , heteroduplex , sister chromatid exchange , homologous chromosome , homologous recombination , microbiology and biotechnology , telomere , gene , chromosome , dna , recombination , karyotype , genetic recombination
Abstract Background Hemophilia A (HA) is an X‐linked 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 shifting‐PCR. The genomic structure was investigated using PCR‐based direct sequencing or quantitative PCR. Results The proband's X chromosome had a 119.5 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 two‐base microhomology, and the centromeric breakpoint was a recombination between F8 intron 1 homologous sequences. The rearrangement mechanism was suggested as a multi‐step rearrangement with template switching such as fork stalling and template switching (FoSTeS)/microhomology‐mediated break‐induced replication (MMBIR) and/or homologous sequence‐associated recombination during a sister chromatid formation. Conclusion We identified the aberrant X chromosome with a split F8 due to a multi‐step rearrangement in a patient with severe HA.