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Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507428/
https://www.ncbi.nlm.nih.gov/pubmed/32627361
http://dx.doi.org/10.1002/mgg3.1390
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author 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
author_facet 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
author_sort Tokoro, Mahiru
collection PubMed
description 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.
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spelling pubmed-75074282020-09-28 Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A 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 Mol Genet Genomic Med Original Articles 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. John Wiley and Sons Inc. 2020-07-05 /pmc/articles/PMC7507428/ /pubmed/32627361 http://dx.doi.org/10.1002/mgg3.1390 Text en © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
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
Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A
title Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A
title_full Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A
title_fullStr Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A
title_full_unstemmed Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A
title_short Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A
title_sort aberrant x chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia a
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507428/
https://www.ncbi.nlm.nih.gov/pubmed/32627361
http://dx.doi.org/10.1002/mgg3.1390
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