{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:48:12Z","timestamp":1788875292796,"version":"build-2803163510"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"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":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Haemophilia B (HB) is associated with pathogenic variants in <jats:italic>F9<\/jats:italic>. Hemizygous deletions encompassing the entire <jats:italic>F9<\/jats:italic> and proximate genes may express extra\u2010haematological clinical phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To analyse the genotype\/phenotype correlations in two unrelated boys with severe early childhood obesity (SCO), global developmental delay (GDD) and similar bleeding phenotype associated with comparable Xq27 deletions spanning the entire <jats:italic>F9<\/jats:italic> and proximate genes, and characterise the pathogenic events estimating the most likely mutational mechanism involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Entire <jats:italic>F9<\/jats:italic>\u2010deletions were detected in three hemizygous unrelated probands with HB: two cases, C#1\/C#2, presented SCO and GDD and a control patient (Co), who only had severe bleeding symptoms. Dense SNP\u2010array and case\u2010specific STS walking scan allowed characterisation of the deletion breakpoints. Extensive use of bioinformatics, statistics and clinical databases allowed the investigation of genotype\u2010phenotype associations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients C#1\/C#2 and Co resulted in a complete <jats:italic>F9<\/jats:italic> and additional gene deletions of variable extensions on Xq26.3\u2010Xq27.2 (C#1\/C#2\/Co: 4.3Mb\/3.9Mb\/160Kb). C#1\/C#2 common deleted gene <jats:italic>SOX3<\/jats:italic> is directly associated with SCO, GDD and pituitary hypothyroidism (PH) whilst C#2 extra\u2010deleted gene <jats:italic>MAGEC2<\/jats:italic> indirectly relates to anal atresia (AA). Breakpoint analysis revealed the involvement of the mechanisms of Alu\/Alu recombination for the first time in HB and non\u2010homologous or alternative end\u2010joining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results represent the first report of unrelated patients with HB, SCO and GDD. This study and the literature update expand the spectrum of clinical findings and molecular insights observed in patients with HB caused by complete <jats:italic>F9<\/jats:italic> and nearby <jats:italic>SOX3<\/jats:italic> and <jats:italic>MAGEC2<\/jats:italic> gene deletions, which may configure a contiguous gene syndrome.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14779","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T19:10:04Z","timestamp":1679080204000},"page":"844-854","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Haemophilia B, severe childhood obesity and other extra\u2010haematological features associated with similar 4Mb\u2010deletions on Xq27: Clinical findings, molecular insights and literature update"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3901-3904","authenticated-orcid":false,"given":"Claudia P.","family":"Radic","sequence":"first","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular de la Hemofilia (GMH) Instituto de Medicina Experimental (IMEX, CONICET\u2010Academia Nacional de Medicina (ANM))  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel M.","family":"Abelleyro","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular de la Hemofilia (GMH) Instituto de Medicina Experimental (IMEX, CONICET\u2010Academia Nacional de Medicina (ANM))  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betiana","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular de la Hemofilia (GMH) Instituto de Medicina Experimental (IMEX, CONICET\u2010Academia Nacional de Medicina (ANM))  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0009-1884","authenticated-orcid":false,"given":"Vanina D.","family":"Marchione","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular de la Hemofilia (GMH) Instituto de Medicina Experimental (IMEX, CONICET\u2010Academia Nacional de Medicina (ANM))  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juli\u00e1n","family":"Nevado","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)\u2010IdiPAZ, Hospital Universitario La Paz Universidad Aut\u00f3noma  Madrid Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras ISCIII  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)\u2010IdiPAZ, Hospital Universitario La Paz Universidad Aut\u00f3noma  Madrid Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras ISCIII  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Sciuccati","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda Hospital de Pediatr\u00eda <i>Prof. Dr Juan P. Garrahan<\/i> (HPJG)  CABA Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8905-140X","authenticated-orcid":false,"given":"Daniela","family":"Neme","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n de la Hemofilia <i>Alfredo Pavlovsky<\/i> (FHAP) Hematology, Soler, Ciudad de Buenos Aires  Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana C.","family":"Rossetti","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular de la Hemofilia (GMH) Instituto de Medicina Experimental (IMEX, CONICET\u2010Academia Nacional de Medicina (ANM))  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Bonduel","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda Hospital de Pediatr\u00eda <i>Prof. Dr Juan P. 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