{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T12:19:54Z","timestamp":1756383594402,"version":"3.41.2"},"reference-count":21,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,7,5]],"date-time":"2020-07-05T00:00:00Z","timestamp":1593907200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Japanese Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","award":["16K09825"],"award-info":[{"award-number":["16K09825"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Japanese Ministry of Health, Labor, and Welfare","award":["2017-012"],"award-info":[{"award-number":["2017-012"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hemophilia A (HA) is an X\u2010linked recessive bleeding disorder caused by pathogenic variants of the coagulation factor VIII gene (<jats:italic>F8<\/jats:italic>). Half of the patients with severe HA have a recurrent inversion in the X chromosome, that is, <jats:italic>F8<\/jats:italic> intron 22 or intron 1 inversion. Here, we characterized an abnormal <jats:italic>F8<\/jats:italic> due to atypical complex X chromosome rearrangements in a Japanese patient with severe HA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Recurrent <jats:italic>F8<\/jats:italic> inversions were tested with inverse shifting\u2010PCR. The genomic structure was investigated using PCR\u2010based direct sequencing or quantitative PCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The proband's X chromosome had a 119.5\u00a0kb insertion, a reverse duplex of an extragenic sequence on the <jats:italic>F8<\/jats:italic> telomere region into the <jats:italic>F8<\/jats:italic> intron 1 with two breakpoints. The telomeric breakpoint was a joining from the <jats:italic>F8<\/jats:italic> intron 1 to the inverted <jats:italic>FUNDC2<\/jats:italic> via a two\u2010base microhomology, and the centromeric breakpoint was a recombination between <jats:italic>F8<\/jats:italic> intron 1 homologous sequences. The rearrangement mechanism was suggested as a multi\u2010step rearrangement with template switching such as fork stalling and template switching (FoSTeS)\/microhomology\u2010mediated break\u2010induced replication (MMBIR) and\/or homologous sequence\u2010associated recombination during a sister chromatid formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified the aberrant X chromosome with a split <jats:italic>F8<\/jats:italic> due to a multi\u2010step rearrangement in a patient with severe HA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1390","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T03:31:25Z","timestamp":1594006285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Aberrant X chromosomal rearrangement through multi\u2010step template switching during sister chromatid formation in a patient with severe hemophilia A"],"prefix":"10.1002","volume":"8","author":[{"given":"Mahiru","family":"Tokoro","sequence":"first","affiliation":[{"name":"Department of Pathophysiological Laboratory Sciences Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4960-1400","authenticated-orcid":false,"given":"Shogo","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Pathophysiological Laboratory Sciences Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuaki","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine Nagoya University Hospital Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misaki","family":"Kakihara","sequence":"additional","affiliation":[{"name":"Department of Pathophysiological Laboratory Sciences Nagoya University 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