{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:08:32Z","timestamp":1793084912108,"version":"4.5.0"},"reference-count":56,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,8,8]],"date-time":"2018-08-08T00:00:00Z","timestamp":1533686400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:p>The distal Xq28 region is very gene\u2010rich, comprising a relatively large number of low\u2010copy repeats (<jats:styled-content style=\"fixed-case\">LCR<\/jats:styled-content>s) predisposing to genomic rearrangements. The best\u2010known rearrangement at this locus is the <jats:italic>F8<\/jats:italic> intron 22 inversion, responsible for up to 45% of severe hemophilia A (<jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>) cases. An additional inversion of intron 1 of <jats:italic>F8<\/jats:italic> has more recently been described, affecting 2%\u20105% of patients with severe <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>. These \u201cbalanced\u201d rearrangements are mediated by intrachromosomal homologous recombination between inversely oriented <jats:styled-content style=\"fixed-case\">LCR<\/jats:styled-content>s located in intron 1 or 22 and other extragenic copies positioned more telomerically outside the <jats:italic>F8<\/jats:italic> gene. The successive innovations of semi\u2010quantitative technologies like multiplex ligation\u2010dependent probe amplification (<jats:styled-content style=\"fixed-case\">MLPA<\/jats:styled-content>) and array comparative genomic hybridization (array <jats:styled-content style=\"fixed-case\">CGH<\/jats:styled-content>) have rendered it possible to highlight a significant number of \u201cunbalanced\u201d rearrangements associated or not with these inversions. Some rearrangements are generated by the non\u2010allelic homologous recombination (<jats:styled-content style=\"fixed-case\">NAHR<\/jats:styled-content>) pathway between directly oriented <jats:styled-content style=\"fixed-case\">LCR<\/jats:styled-content>s. Others are probably the result of unequal crossing\u2010over or U\u2010loop exchanges during female meiosis. This review sought to provide an overview of the mechanisms underlying rearrangements at the distal Xq28 locus and discuss their clinical impacts other than <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>, such as risks of developing high inhibitor levels and spontaneous abortion, as well as other pathologies like cardiovascular disease or potentially X\u2010linked intellectual disease.<\/jats:p>","DOI":"10.1111\/hae.13569","type":"journal-article","created":{"date-parts":[[2018,8,8]],"date-time":"2018-08-08T09:25:11Z","timestamp":1533720311000},"page":"711-719","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Review of molecular mechanisms at distal Xq28 leading to balanced or unbalanced genomic rearrangements and their phenotypic impacts on 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