{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:47:55Z","timestamp":1790729275792,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,9,4]],"date-time":"2021-09-04T00:00:00Z","timestamp":1630713600000},"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":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Depending on the location of insertion of the gained region, <jats:italic>F8<\/jats:italic> duplications can have variable clinical impacts from benign impact to severe haemophilia A phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To characterize two large Xq28 duplications involving F8 incidentally detected by chromosome microarray analysis (CMA) in two patients presenting severe intellectual disability but no history of bleeding disorder.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole genome sequencing (WGS) was performed in order to characterize the two large Xq28 duplications at nucleotide level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In patient 1, a 60\u201373\u00a0kb gained region encompassing the exons 23\u201326 of <jats:italic>F8<\/jats:italic> and <jats:italic>SMIM9<\/jats:italic> was inserted at the int22h\u20102 locus following a non\u2010homologous recombination between int22h\u20101 and int22h\u20102. We hypothesized that two independent events, micro\u2010homology\u2010mediated break\u2010induced replication (MMBIR) and break\u2010induced replication (BIR), could be involved in this rearrangement. In patient 2, the CMA found duplication from 101 to 116\u2010kb long encompassing the exons 16\u201326 of <jats:italic>F8<\/jats:italic> and <jats:italic>SMIM9<\/jats:italic>. The WGS analysis identified a more complex rearrangement with the presence of three genomic junctions. Due to the multiple micro\u2010homologies observed at breakpoints, a replication\u2010based mechanism such as fork stalling and template switching (FoSTeS) was greatly suspected. In both cases, these complex rearrangements preserved an intact copy of the <jats:italic>F8<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study highlights the value of WGS to characterize the genomic junction at the nucleotide level and ultimately better describe the molecular mechanisms involved in Xq28 structural variations. It also emphasizes the importance of specifying the structure of the genomic gain in order to improve genotype\u2010phenotype correlation and genetic counselling.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14402","type":"journal-article","created":{"date-parts":[[2021,9,4]],"date-time":"2021-09-04T17:43:37Z","timestamp":1630777417000},"page":"117-124","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Complete characterisation of two new large Xq28 duplications involving <i>F8<\/i> using whole genome sequencing in patients without haemophilia A"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7408-6474","authenticated-orcid":false,"given":"Yohann","family":"Jourdy","sequence":"first","affiliation":[{"name":"Hospices Civils de Lyon Groupe Hospitalier Est Service d'h\u00e9matologie Biologique  Bron France"},{"name":"UR 4609 H\u00e9mostase et thrombose Universit\u00e9 Claude Bernard 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