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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Copy-Number Gains of <italic>HUWE1</italic> Due to Replication- and Recombination-Based Rearrangements</title><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Belet, Stefanie" sort="Belet, Stefanie" uniqKey="Belet S" first="Stefanie" last="Belet">Stefanie Belet</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Martinez, Francisco" sort="Martinez, Francisco" uniqKey="Martinez F" first="Francisco" last="Martinez">Francisco Martinez</name><affiliation><nlm:aff id="aff3">Genetics Unit, Hospital Universitario La Fe, 46009 Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Santos Reboucas, Cintia Barros" sort="Santos Reboucas, Cintia Barros" uniqKey="Santos Reboucas C" first="Cíntia Barros" last="Santos-Rebouças">Cíntia Barros Santos-Rebouças</name><affiliation><nlm:aff id="aff4">Departement of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Declercq, Matthias" sort="Declercq, Matthias" uniqKey="Declercq M" first="Matthias" last="Declercq">Matthias Declercq</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Verbeeck, Jelle" sort="Verbeeck, Jelle" uniqKey="Verbeeck J" first="Jelle" last="Verbeeck">Jelle Verbeeck</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Donckers, Lene" sort="Donckers, Lene" uniqKey="Donckers L" first="Lene" last="Donckers">Lene Donckers</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Berland, Siren" sort="Berland, Siren" uniqKey="Berland S" first="Siren" last="Berland">Siren Berland</name><affiliation><nlm:aff id="aff5">Department of Clinical Genetics, St. Olav's Hospital, 7018 Trondheim, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen, 5021 Bergen, Norway</nlm:aff></affiliation></author><author><name sortKey="Mayo, Sonia" sort="Mayo, Sonia" uniqKey="Mayo S" first="Sonia" last="Mayo">Sonia Mayo</name><affiliation><nlm:aff id="aff3">Genetics Unit, Hospital Universitario La Fe, 46009 Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Rosello, Monica" sort="Rosello, Monica" uniqKey="Rosello M" first="Monica" last="Rosello">Monica Rosello</name><affiliation><nlm:aff id="aff3">Genetics Unit, Hospital Universitario La Fe, 46009 Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Pimentel, Marcia Mattos Goncalves" sort="Pimentel, Marcia Mattos Goncalves" uniqKey="Pimentel M" first="Márcia Mattos Gonçalves" last="Pimentel">Márcia Mattos Gonçalves Pimentel</name><affiliation><nlm:aff id="aff4">Departement of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Fintelman Rodrigues, Natalia" sort="Fintelman Rodrigues, Natalia" uniqKey="Fintelman Rodrigues N" first="Natalia" last="Fintelman-Rodrigues">Natalia Fintelman-Rodrigues</name><affiliation><nlm:aff id="aff4">Departement of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Hovland, Randi" sort="Hovland, Randi" uniqKey="Hovland R" first="Randi" last="Hovland">Randi Hovland</name><affiliation><nlm:aff id="aff6">Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen, 5021 Bergen, Norway</nlm:aff></affiliation></author><author><name sortKey="Rodrigues Dos Santos, Suely" sort="Rodrigues Dos Santos, Suely" uniqKey="Rodrigues Dos Santos S" first="Suely" last="Rodrigues Dos Santos">Suely Rodrigues Dos Santos</name><affiliation><nlm:aff id="aff7">Gaffrée and Guinle University Hospital, Federal University of Rio de Janeiro State, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F. Lucy" last="Raymond">F. Lucy Raymond</name><affiliation><nlm:aff id="aff8">Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK</nlm:aff></affiliation></author><author><name sortKey="Bose, Tulika" sort="Bose, Tulika" uniqKey="Bose T" first="Tulika" last="Bose">Tulika Bose</name><affiliation><nlm:aff id="aff9">Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Level 9, Clarence Rieger Building, North Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Corbett, Mark A" sort="Corbett, Mark A" uniqKey="Corbett M" first="Mark A." last="Corbett">Mark A. Corbett</name><affiliation><nlm:aff id="aff9">Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Level 9, Clarence Rieger Building, North Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Sheffield, Leslie" sort="Sheffield, Leslie" uniqKey="Sheffield L" first="Leslie" last="Sheffield">Leslie Sheffield</name><affiliation><nlm:aff id="aff9">Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Level 9, Clarence Rieger Building, North Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Van Ravenswaaij Arts, Conny M A" sort="Van Ravenswaaij Arts, Conny M A" uniqKey="Van Ravenswaaij Arts C" first="Conny M. A." last="Van Ravenswaaij-Arts">Conny M. A. Van Ravenswaaij-Arts</name><affiliation><nlm:aff id="aff10">Department Genetics, University Medical Center Groningen, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dijkhuizen, Trijnie" sort="Dijkhuizen, Trijnie" uniqKey="Dijkhuizen T" first="Trijnie" last="Dijkhuizen">Trijnie Dijkhuizen</name><affiliation><nlm:aff id="aff10">Department Genetics, University Medical Center Groningen, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Coutton, Charles" sort="Coutton, Charles" uniqKey="Coutton C" first="Charles" last="Coutton">Charles Coutton</name><affiliation><nlm:aff id="aff11">Laboratoire de Génétique Chromosomique, Département de Génétique et Procréation, Hôpital Couple Enfant, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Equipe Génétique, Infertilité et Thérapeutique, Laboratoire AGIM, FRE3405, Centre National de la Recherche Scientifique, 38706 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Université Joseph Fourier, Domaine de la Merci, 38706 Grenoble, France</nlm:aff></affiliation></author><author><name sortKey="Satre, Veronique" sort="Satre, Veronique" uniqKey="Satre V" first="Veronique" last="Satre">Veronique Satre</name><affiliation><nlm:aff id="aff11">Laboratoire de Génétique Chromosomique, Département de Génétique et Procréation, Hôpital Couple Enfant, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Equipe Génétique, Infertilité et Thérapeutique, Laboratoire AGIM, FRE3405, Centre National de la Recherche Scientifique, 38706 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Université Joseph Fourier, Domaine de la Merci, 38706 Grenoble, France</nlm:aff></affiliation></author><author><name sortKey="Siu, Victoria" sort="Siu, Victoria" uniqKey="Siu V" first="Victoria" last="Siu">Victoria Siu</name><affiliation><nlm:aff id="aff14">Department of Pediatrics, University of Western Ontario, London, Ontario N6C 2V5, Canada</nlm:aff></affiliation></author><author><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22840365</idno><idno type="pmc">3415555</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415555</idno><idno type="RBID">PMC:3415555</idno><idno type="doi">10.1016/j.ajhg.2012.06.010</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001681</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001681</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Copy-Number Gains of <italic>HUWE1</italic> Due to Replication- and Recombination-Based Rearrangements</title><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Belet, Stefanie" sort="Belet, Stefanie" uniqKey="Belet S" first="Stefanie" last="Belet">Stefanie Belet</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Martinez, Francisco" sort="Martinez, Francisco" uniqKey="Martinez F" first="Francisco" last="Martinez">Francisco Martinez</name><affiliation><nlm:aff id="aff3">Genetics Unit, Hospital Universitario La Fe, 46009 Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Santos Reboucas, Cintia Barros" sort="Santos Reboucas, Cintia Barros" uniqKey="Santos Reboucas C" first="Cíntia Barros" last="Santos-Rebouças">Cíntia Barros Santos-Rebouças</name><affiliation><nlm:aff id="aff4">Departement of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Declercq, Matthias" sort="Declercq, Matthias" uniqKey="Declercq M" first="Matthias" last="Declercq">Matthias Declercq</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Verbeeck, Jelle" sort="Verbeeck, Jelle" uniqKey="Verbeeck J" first="Jelle" last="Verbeeck">Jelle Verbeeck</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Donckers, Lene" sort="Donckers, Lene" uniqKey="Donckers L" first="Lene" last="Donckers">Lene Donckers</name><affiliation><nlm:aff id="aff1">Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Berland, Siren" sort="Berland, Siren" uniqKey="Berland S" first="Siren" last="Berland">Siren Berland</name><affiliation><nlm:aff id="aff5">Department of Clinical Genetics, St. Olav's Hospital, 7018 Trondheim, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen, 5021 Bergen, Norway</nlm:aff></affiliation></author><author><name sortKey="Mayo, Sonia" sort="Mayo, Sonia" uniqKey="Mayo S" first="Sonia" last="Mayo">Sonia Mayo</name><affiliation><nlm:aff id="aff3">Genetics Unit, Hospital Universitario La Fe, 46009 Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Rosello, Monica" sort="Rosello, Monica" uniqKey="Rosello M" first="Monica" last="Rosello">Monica Rosello</name><affiliation><nlm:aff id="aff3">Genetics Unit, Hospital Universitario La Fe, 46009 Valencia, Spain</nlm:aff></affiliation></author><author><name sortKey="Pimentel, Marcia Mattos Goncalves" sort="Pimentel, Marcia Mattos Goncalves" uniqKey="Pimentel M" first="Márcia Mattos Gonçalves" last="Pimentel">Márcia Mattos Gonçalves Pimentel</name><affiliation><nlm:aff id="aff4">Departement of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Fintelman Rodrigues, Natalia" sort="Fintelman Rodrigues, Natalia" uniqKey="Fintelman Rodrigues N" first="Natalia" last="Fintelman-Rodrigues">Natalia Fintelman-Rodrigues</name><affiliation><nlm:aff id="aff4">Departement of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Hovland, Randi" sort="Hovland, Randi" uniqKey="Hovland R" first="Randi" last="Hovland">Randi Hovland</name><affiliation><nlm:aff id="aff6">Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen, 5021 Bergen, Norway</nlm:aff></affiliation></author><author><name sortKey="Rodrigues Dos Santos, Suely" sort="Rodrigues Dos Santos, Suely" uniqKey="Rodrigues Dos Santos S" first="Suely" last="Rodrigues Dos Santos">Suely Rodrigues Dos Santos</name><affiliation><nlm:aff id="aff7">Gaffrée and Guinle University Hospital, Federal University of Rio de Janeiro State, Rio de Janeiro 20550-013, Brazil</nlm:aff></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F. Lucy" last="Raymond">F. Lucy Raymond</name><affiliation><nlm:aff id="aff8">Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK</nlm:aff></affiliation></author><author><name sortKey="Bose, Tulika" sort="Bose, Tulika" uniqKey="Bose T" first="Tulika" last="Bose">Tulika Bose</name><affiliation><nlm:aff id="aff9">Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Level 9, Clarence Rieger Building, North Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Corbett, Mark A" sort="Corbett, Mark A" uniqKey="Corbett M" first="Mark A." last="Corbett">Mark A. Corbett</name><affiliation><nlm:aff id="aff9">Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Level 9, Clarence Rieger Building, North Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Sheffield, Leslie" sort="Sheffield, Leslie" uniqKey="Sheffield L" first="Leslie" last="Sheffield">Leslie Sheffield</name><affiliation><nlm:aff id="aff9">Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Level 9, Clarence Rieger Building, North Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Van Ravenswaaij Arts, Conny M A" sort="Van Ravenswaaij Arts, Conny M A" uniqKey="Van Ravenswaaij Arts C" first="Conny M. A." last="Van Ravenswaaij-Arts">Conny M. A. Van Ravenswaaij-Arts</name><affiliation><nlm:aff id="aff10">Department Genetics, University Medical Center Groningen, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dijkhuizen, Trijnie" sort="Dijkhuizen, Trijnie" uniqKey="Dijkhuizen T" first="Trijnie" last="Dijkhuizen">Trijnie Dijkhuizen</name><affiliation><nlm:aff id="aff10">Department Genetics, University Medical Center Groningen, 9700 RB Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Coutton, Charles" sort="Coutton, Charles" uniqKey="Coutton C" first="Charles" last="Coutton">Charles Coutton</name><affiliation><nlm:aff id="aff11">Laboratoire de Génétique Chromosomique, Département de Génétique et Procréation, Hôpital Couple Enfant, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Equipe Génétique, Infertilité et Thérapeutique, Laboratoire AGIM, FRE3405, Centre National de la Recherche Scientifique, 38706 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Université Joseph Fourier, Domaine de la Merci, 38706 Grenoble, France</nlm:aff></affiliation></author><author><name sortKey="Satre, Veronique" sort="Satre, Veronique" uniqKey="Satre V" first="Veronique" last="Satre">Veronique Satre</name><affiliation><nlm:aff id="aff11">Laboratoire de Génétique Chromosomique, Département de Génétique et Procréation, Hôpital Couple Enfant, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Equipe Génétique, Infertilité et Thérapeutique, Laboratoire AGIM, FRE3405, Centre National de la Recherche Scientifique, 38706 Grenoble, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Université Joseph Fourier, Domaine de la Merci, 38706 Grenoble, France</nlm:aff></affiliation></author><author><name sortKey="Siu, Victoria" sort="Siu, Victoria" uniqKey="Siu V" first="Victoria" last="Siu">Victoria Siu</name><affiliation><nlm:aff id="aff14">Department of Pediatrics, University of Western Ontario, London, Ontario N6C 2V5, Canada</nlm:aff></affiliation></author><author><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name><affiliation><nlm:aff id="aff2">Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring <italic>HSD17B10</italic>, <italic>HUWE1</italic>, and the microRNAs <italic>miR-98</italic> and <italic>let-7f-2</italic> in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the <italic>HUWE1</italic> locus only. Consequently, increased mRNA levels were detected for <italic>HUWE1</italic>, but not <italic>HSD17B10</italic>. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of <italic>HUWE1</italic> (exon 28 to 3′ untranslated region), including <italic>miR-98</italic> and <italic>let-7f-2</italic>. Our findings thus demonstrate that <italic>HUWE1</italic> is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of <italic>HUWE1</italic>-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial <italic>HUWE1</italic> copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of <italic>HUWE1</italic> causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22840365</article-id><article-id pub-id-type="pmc">3415555</article-id><article-id pub-id-type="publisher-id">AJHG1192</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2012.06.010</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Copy-Number Gains of <italic>HUWE1</italic> Due to Replication- and Recombination-Based Rearrangements</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Froyen</surname><given-names>Guy</given-names></name><email>guy.froyen@cme.vib-kuleuven.be</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Belet</surname><given-names>Stefanie</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Martinez</surname><given-names>Francisco</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Santos-Rebouças</surname><given-names>Cíntia Barros</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Declercq</surname><given-names>Matthias</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Verbeeck</surname><given-names>Jelle</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Donckers</surname><given-names>Lene</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Berland</surname><given-names>Siren</given-names></name><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Mayo</surname><given-names>Sonia</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Rosello</surname><given-names>Monica</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Pimentel</surname><given-names>Márcia Mattos Gonçalves</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Fintelman-Rodrigues</surname><given-names>Natalia</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Hovland</surname><given-names>Randi</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Rodrigues dos Santos</surname><given-names>Suely</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Raymond</surname><given-names>F. Lucy</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Bose</surname><given-names>Tulika</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Corbett</surname><given-names>Mark A.</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Sheffield</surname><given-names>Leslie</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>van Ravenswaaij-Arts</surname><given-names>Conny M.A.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Dijkhuizen</surname><given-names>Trijnie</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Coutton</surname><given-names>Charles</given-names></name><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff12" ref-type="aff">12</xref><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Satre</surname><given-names>Veronique</given-names></name><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff12" ref-type="aff">12</xref><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Siu</surname><given-names>Victoria</given-names></name><xref rid="aff14" ref-type="aff">14</xref></contrib><contrib contrib-type="author"><name><surname>Marynen</surname><given-names>Peter</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium</aff><aff id="aff2"><label>2</label>Human Genome Laboratory, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium</aff><aff id="aff3"><label>3</label>Genetics Unit, Hospital Universitario La Fe, 46009 Valencia, Spain</aff><aff id="aff4"><label>4</label>Departement of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil</aff><aff id="aff5"><label>5</label>Department of Clinical Genetics, St. Olav's Hospital, 7018 Trondheim, Norway</aff><aff id="aff6"><label>6</label>Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen, 5021 Bergen, Norway</aff><aff id="aff7"><label>7</label>Gaffrée and Guinle University Hospital, Federal University of Rio de Janeiro State, Rio de Janeiro 20550-013, Brazil</aff><aff id="aff8"><label>8</label>Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK</aff><aff id="aff9"><label>9</label>Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, Level 9, Clarence Rieger Building, North Adelaide, South Australia 5006, Australia</aff><aff id="aff10"><label>10</label>Department Genetics, University Medical Center Groningen, 9700 RB Groningen, The Netherlands</aff><aff id="aff11"><label>11</label>Laboratoire de Génétique Chromosomique, Département de Génétique et Procréation, Hôpital Couple Enfant, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France</aff><aff id="aff12"><label>12</label>Equipe Génétique, Infertilité et Thérapeutique, Laboratoire AGIM, FRE3405, Centre National de la Recherche Scientifique, 38706 Grenoble, France</aff><aff id="aff13"><label>13</label>Université Joseph Fourier, Domaine de la Merci, 38706 Grenoble, France</aff><aff id="aff14"><label>14</label>Department of Pediatrics, University of Western Ontario, London, Ontario N6C 2V5, Canada</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>guy.froyen@cme.vib-kuleuven.be</email></corresp></author-notes><pub-date pub-type="ppub"><day>10</day><month>8</month><year>2012</year></pub-date><volume>91</volume><issue>2</issue><fpage>252</fpage><lpage>264</lpage><history><date date-type="received"><day>24</day><month>4</month><year>2012</year></date><date date-type="rev-recd"><day>21</day><month>5</month><year>2012</year></date><date date-type="accepted"><day>21</day><month>6</month><year>2012</year></date></history><permissions><copyright-statement>© 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring <italic>HSD17B10</italic>, <italic>HUWE1</italic>, and the microRNAs <italic>miR-98</italic> and <italic>let-7f-2</italic> in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the <italic>HUWE1</italic> locus only. Consequently, increased mRNA levels were detected for <italic>HUWE1</italic>, but not <italic>HSD17B10</italic>. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of <italic>HUWE1</italic> (exon 28 to 3′ untranslated region), including <italic>miR-98</italic> and <italic>let-7f-2</italic>. Our findings thus demonstrate that <italic>HUWE1</italic> is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of <italic>HUWE1</italic>-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial <italic>HUWE1</italic> copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of <italic>HUWE1</italic> causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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