Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.
Identifieur interne : 002616 ( PubMed/Corpus ); précédent : 002615; suivant : 002617Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.
Auteurs : Raman Kumar ; Mark A. Corbett ; Bregje W M. Van Bon ; Alison Gardner ; Joshua A. Woenig ; Lachlan A. Jolly ; Evelyn Douglas ; Kathryn Friend ; Chuan Tan ; Hilde Van Esch ; Maureen Holvoet ; Martine Raynaud ; Michael Field ; Melanie Leffler ; Bartłomiej Budny ; Marzena Wisniewska ; Magdalena Badura-Stronka ; Anna Latos-Biele Ska ; Jacqueline Batanian ; Jill A. Rosenfeld ; Lina Basel-Vanagaite ; Corinna Jensen ; Melanie Bienek ; Guy Froyen ; Reinhard Ullmann ; Hao Hu ; Michael I. Love ; Stefan A. Haas ; Pawel Stankiewicz ; Sau Wai Cheung ; Anne Baxendale ; Jillian Nicholl ; Elizabeth M. Thompson ; Eric Haan ; Vera M. Kalscheuer ; Jozef GeczSource :
- Human molecular genetics [ 1460-2083 ] ; 2015.
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : Antigens, Nuclear.
- genetics : Chromosomes, Human, X, DNA Copy Number Variations, Intellectual Disability.
- Humans, Male, Problem Behavior, Reverse Transcriptase Polymerase Chain Reaction.
Abstract
Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.
DOI: 10.1093/hmg/ddv414
PubMed: 26443594
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pubmed:26443594Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.</title><author><name sortKey="Kumar, Raman" sort="Kumar, Raman" uniqKey="Kumar R" first="Raman" last="Kumar">Raman Kumar</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></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:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Van Bon, Bregje W M" sort="Van Bon, Bregje W M" uniqKey="Van Bon B" first="Bregje W M" last="Van Bon">Bregje W M. Van Bon</name><affiliation><nlm:affiliation>Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Gardner, Alison" sort="Gardner, Alison" uniqKey="Gardner A" first="Alison" last="Gardner">Alison Gardner</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Woenig, Joshua A" sort="Woenig, Joshua A" uniqKey="Woenig J" first="Joshua A" last="Woenig">Joshua A. Woenig</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Jolly, Lachlan A" sort="Jolly, Lachlan A" uniqKey="Jolly L" first="Lachlan A" last="Jolly">Lachlan A. Jolly</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Douglas, Evelyn" sort="Douglas, Evelyn" uniqKey="Douglas E" first="Evelyn" last="Douglas">Evelyn Douglas</name><affiliation><nlm:affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Friend, Kathryn" sort="Friend, Kathryn" uniqKey="Friend K" first="Kathryn" last="Friend">Kathryn Friend</name><affiliation><nlm:affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Tan, Chuan" sort="Tan, Chuan" uniqKey="Tan C" first="Chuan" last="Tan">Chuan Tan</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name><affiliation><nlm:affiliation>Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Holvoet, Maureen" sort="Holvoet, Maureen" uniqKey="Holvoet M" first="Maureen" last="Holvoet">Maureen Holvoet</name><affiliation><nlm:affiliation>Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name><affiliation><nlm:affiliation>Centre Hospitalier Régional Universitaire, Service de Génétique, 37000 Tours, France.</nlm:affiliation></affiliation></author><author><name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name><affiliation><nlm:affiliation>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Leffler, Melanie" sort="Leffler, Melanie" uniqKey="Leffler M" first="Melanie" last="Leffler">Melanie Leffler</name><affiliation><nlm:affiliation>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Budny, Bartlomiej" sort="Budny, Bartlomiej" uniqKey="Budny B" first="Bartłomiej" last="Budny">Bartłomiej Budny</name><affiliation><nlm:affiliation>Department of Endocrinology, Metabolism and Internal Diseases and.</nlm:affiliation></affiliation></author><author><name sortKey="Wisniewska, Marzena" sort="Wisniewska, Marzena" uniqKey="Wisniewska M" first="Marzena" last="Wisniewska">Marzena Wisniewska</name><affiliation><nlm:affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Badura Stronka, Magdalena" sort="Badura Stronka, Magdalena" uniqKey="Badura Stronka M" first="Magdalena" last="Badura-Stronka">Magdalena Badura-Stronka</name><affiliation><nlm:affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Latos Biele Ska, Anna" sort="Latos Biele Ska, Anna" uniqKey="Latos Biele Ska A" first="Anna" last="Latos-Biele Ska">Anna Latos-Biele Ska</name><affiliation><nlm:affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Batanian, Jacqueline" sort="Batanian, Jacqueline" uniqKey="Batanian J" first="Jacqueline" last="Batanian">Jacqueline Batanian</name><affiliation><nlm:affiliation>Department of Pediatrics, Saint Louis University, St Louis, MO 63104, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A" last="Rosenfeld">Jill A. Rosenfeld</name><affiliation><nlm:affiliation>Signature Genomic Laboratories, Spokane, WA 99207, USA, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Basel Vanagaite, Lina" sort="Basel Vanagaite, Lina" uniqKey="Basel Vanagaite L" first="Lina" last="Basel-Vanagaite">Lina Basel-Vanagaite</name><affiliation><nlm:affiliation>Raphael Recanati Genetic Institute and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.</nlm:affiliation></affiliation></author><author><name sortKey="Jensen, Corinna" sort="Jensen, Corinna" uniqKey="Jensen C" first="Corinna" last="Jensen">Corinna Jensen</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Bienek, Melanie" sort="Bienek, Melanie" uniqKey="Bienek M" first="Melanie" last="Bienek">Melanie Bienek</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation><nlm:affiliation>Human Genome Laboratory, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium and.</nlm:affiliation></affiliation></author><author><name sortKey="Ullmann, Reinhard" sort="Ullmann, Reinhard" uniqKey="Ullmann R" first="Reinhard" last="Ullmann">Reinhard Ullmann</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and, Bundeswehr Institute of Radiobiology, 80937 Munich, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Hu, Hao" sort="Hu, Hao" uniqKey="Hu H" first="Hao" last="Hu">Hao Hu</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Love, Michael I" sort="Love, Michael I" uniqKey="Love M" first="Michael I" last="Love">Michael I. Love</name><affiliation><nlm:affiliation>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Haas, Stefan A" sort="Haas, Stefan A" uniqKey="Haas S" first="Stefan A" last="Haas">Stefan A. Haas</name><affiliation><nlm:affiliation>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Stankiewicz, Pawel" sort="Stankiewicz, Pawel" uniqKey="Stankiewicz P" first="Pawel" last="Stankiewicz">Pawel Stankiewicz</name><affiliation><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cheung, Sau Wai" sort="Cheung, Sau Wai" uniqKey="Cheung S" first="Sau Wai" last="Cheung">Sau Wai Cheung</name><affiliation><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Baxendale, Anne" sort="Baxendale, Anne" uniqKey="Baxendale A" first="Anne" last="Baxendale">Anne Baxendale</name><affiliation><nlm:affiliation>South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Nicholl, Jillian" sort="Nicholl, Jillian" uniqKey="Nicholl J" first="Jillian" last="Nicholl">Jillian Nicholl</name><affiliation><nlm:affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Thompson, Elizabeth M" sort="Thompson, Elizabeth M" uniqKey="Thompson E" first="Elizabeth M" last="Thompson">Elizabeth M. Thompson</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Kalscheuer, Vera M" sort="Kalscheuer, Vera M" uniqKey="Kalscheuer V" first="Vera M" last="Kalscheuer">Vera M. Kalscheuer</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, jozef.gecz@adelaide.edu.au.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26443594</idno><idno type="pmid">26443594</idno><idno type="doi">10.1093/hmg/ddv414</idno><idno type="wicri:Area/PubMed/Corpus">002616</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002616</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.</title><author><name sortKey="Kumar, Raman" sort="Kumar, Raman" uniqKey="Kumar R" first="Raman" last="Kumar">Raman Kumar</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></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:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Van Bon, Bregje W M" sort="Van Bon, Bregje W M" uniqKey="Van Bon B" first="Bregje W M" last="Van Bon">Bregje W M. Van Bon</name><affiliation><nlm:affiliation>Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Gardner, Alison" sort="Gardner, Alison" uniqKey="Gardner A" first="Alison" last="Gardner">Alison Gardner</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Woenig, Joshua A" sort="Woenig, Joshua A" uniqKey="Woenig J" first="Joshua A" last="Woenig">Joshua A. Woenig</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Jolly, Lachlan A" sort="Jolly, Lachlan A" uniqKey="Jolly L" first="Lachlan A" last="Jolly">Lachlan A. Jolly</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Douglas, Evelyn" sort="Douglas, Evelyn" uniqKey="Douglas E" first="Evelyn" last="Douglas">Evelyn Douglas</name><affiliation><nlm:affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Friend, Kathryn" sort="Friend, Kathryn" uniqKey="Friend K" first="Kathryn" last="Friend">Kathryn Friend</name><affiliation><nlm:affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Tan, Chuan" sort="Tan, Chuan" uniqKey="Tan C" first="Chuan" last="Tan">Chuan Tan</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name><affiliation><nlm:affiliation>Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Holvoet, Maureen" sort="Holvoet, Maureen" uniqKey="Holvoet M" first="Maureen" last="Holvoet">Maureen Holvoet</name><affiliation><nlm:affiliation>Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name><affiliation><nlm:affiliation>Centre Hospitalier Régional Universitaire, Service de Génétique, 37000 Tours, France.</nlm:affiliation></affiliation></author><author><name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name><affiliation><nlm:affiliation>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Leffler, Melanie" sort="Leffler, Melanie" uniqKey="Leffler M" first="Melanie" last="Leffler">Melanie Leffler</name><affiliation><nlm:affiliation>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Budny, Bartlomiej" sort="Budny, Bartlomiej" uniqKey="Budny B" first="Bartłomiej" last="Budny">Bartłomiej Budny</name><affiliation><nlm:affiliation>Department of Endocrinology, Metabolism and Internal Diseases and.</nlm:affiliation></affiliation></author><author><name sortKey="Wisniewska, Marzena" sort="Wisniewska, Marzena" uniqKey="Wisniewska M" first="Marzena" last="Wisniewska">Marzena Wisniewska</name><affiliation><nlm:affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Badura Stronka, Magdalena" sort="Badura Stronka, Magdalena" uniqKey="Badura Stronka M" first="Magdalena" last="Badura-Stronka">Magdalena Badura-Stronka</name><affiliation><nlm:affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Latos Biele Ska, Anna" sort="Latos Biele Ska, Anna" uniqKey="Latos Biele Ska A" first="Anna" last="Latos-Biele Ska">Anna Latos-Biele Ska</name><affiliation><nlm:affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Batanian, Jacqueline" sort="Batanian, Jacqueline" uniqKey="Batanian J" first="Jacqueline" last="Batanian">Jacqueline Batanian</name><affiliation><nlm:affiliation>Department of Pediatrics, Saint Louis University, St Louis, MO 63104, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A" last="Rosenfeld">Jill A. Rosenfeld</name><affiliation><nlm:affiliation>Signature Genomic Laboratories, Spokane, WA 99207, USA, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Basel Vanagaite, Lina" sort="Basel Vanagaite, Lina" uniqKey="Basel Vanagaite L" first="Lina" last="Basel-Vanagaite">Lina Basel-Vanagaite</name><affiliation><nlm:affiliation>Raphael Recanati Genetic Institute and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.</nlm:affiliation></affiliation></author><author><name sortKey="Jensen, Corinna" sort="Jensen, Corinna" uniqKey="Jensen C" first="Corinna" last="Jensen">Corinna Jensen</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Bienek, Melanie" sort="Bienek, Melanie" uniqKey="Bienek M" first="Melanie" last="Bienek">Melanie Bienek</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation><nlm:affiliation>Human Genome Laboratory, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium and.</nlm:affiliation></affiliation></author><author><name sortKey="Ullmann, Reinhard" sort="Ullmann, Reinhard" uniqKey="Ullmann R" first="Reinhard" last="Ullmann">Reinhard Ullmann</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and, Bundeswehr Institute of Radiobiology, 80937 Munich, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Hu, Hao" sort="Hu, Hao" uniqKey="Hu H" first="Hao" last="Hu">Hao Hu</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Love, Michael I" sort="Love, Michael I" uniqKey="Love M" first="Michael I" last="Love">Michael I. Love</name><affiliation><nlm:affiliation>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Haas, Stefan A" sort="Haas, Stefan A" uniqKey="Haas S" first="Stefan A" last="Haas">Stefan A. Haas</name><affiliation><nlm:affiliation>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Stankiewicz, Pawel" sort="Stankiewicz, Pawel" uniqKey="Stankiewicz P" first="Pawel" last="Stankiewicz">Pawel Stankiewicz</name><affiliation><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cheung, Sau Wai" sort="Cheung, Sau Wai" uniqKey="Cheung S" first="Sau Wai" last="Cheung">Sau Wai Cheung</name><affiliation><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Baxendale, Anne" sort="Baxendale, Anne" uniqKey="Baxendale A" first="Anne" last="Baxendale">Anne Baxendale</name><affiliation><nlm:affiliation>South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Nicholl, Jillian" sort="Nicholl, Jillian" uniqKey="Nicholl J" first="Jillian" last="Nicholl">Jillian Nicholl</name><affiliation><nlm:affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Thompson, Elizabeth M" sort="Thompson, Elizabeth M" uniqKey="Thompson E" first="Elizabeth M" last="Thompson">Elizabeth M. Thompson</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Kalscheuer, Vera M" sort="Kalscheuer, Vera M" uniqKey="Kalscheuer V" first="Vera M" last="Kalscheuer">Vera M. Kalscheuer</name><affiliation><nlm:affiliation>Department of Human Molecular Genetics and.</nlm:affiliation></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, jozef.gecz@adelaide.edu.au.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antigens, Nuclear (genetics)</term><term>Chromosomes, Human, X (genetics)</term><term>DNA Copy Number Variations (genetics)</term><term>Humans</term><term>Intellectual Disability (genetics)</term><term>Male</term><term>Problem Behavior</term><term>Reverse Transcriptase Polymerase Chain Reaction</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antigens, Nuclear</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Chromosomes, Human, X</term><term>DNA Copy Number Variations</term><term>Intellectual Disability</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Male</term><term>Problem Behavior</term><term>Reverse Transcriptase Polymerase Chain Reaction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26443594</PMID><DateCreated><Year>2015</Year><Month>12</Month><Day>01</Day></DateCreated><DateCompleted><Year>2016</Year><Month>09</Month><Day>20</Day></DateCompleted><DateRevised><Year>2015</Year><Month>12</Month><Day>01</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2083</ISSN><JournalIssue CitedMedium="Internet"><Volume>24</Volume><Issue>25</Issue><PubDate><Year>2015</Year><Month>Dec</Month><Day>20</Day></PubDate></JournalIssue><Title>Human molecular genetics</Title><ISOAbbreviation>Hum. Mol. Genet.</ISOAbbreviation></Journal><ArticleTitle>Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.</ArticleTitle><Pagination><MedlinePgn>7171-81</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/hmg/ddv414</ELocationID><Abstract><AbstractText>Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.</AbstractText><CopyrightInformation>© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kumar</LastName><ForeName>Raman</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Corbett</LastName><ForeName>Mark A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Van Bon</LastName><ForeName>Bregje W M</ForeName><Initials>BW</Initials><AffiliationInfo><Affiliation>Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gardner</LastName><ForeName>Alison</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Woenig</LastName><ForeName>Joshua A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jolly</LastName><ForeName>Lachlan A</ForeName><Initials>LA</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Douglas</LastName><ForeName>Evelyn</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Friend</LastName><ForeName>Kathryn</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tan</LastName><ForeName>Chuan</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Van Esch</LastName><ForeName>Hilde</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Holvoet</LastName><ForeName>Maureen</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Raynaud</LastName><ForeName>Martine</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Centre Hospitalier Régional Universitaire, Service de Génétique, 37000 Tours, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Field</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leffler</LastName><ForeName>Melanie</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Budny</LastName><ForeName>Bartłomiej</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Department of Endocrinology, Metabolism and Internal Diseases and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wisniewska</LastName><ForeName>Marzena</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Badura-Stronka</LastName><ForeName>Magdalena</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Latos-Bieleńska</LastName><ForeName>Anna</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Batanian</LastName><ForeName>Jacqueline</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Saint Louis University, St Louis, MO 63104, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rosenfeld</LastName><ForeName>Jill A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Signature Genomic Laboratories, Spokane, WA 99207, USA, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Basel-Vanagaite</LastName><ForeName>Lina</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Raphael Recanati Genetic Institute and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jensen</LastName><ForeName>Corinna</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Human Molecular Genetics and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bienek</LastName><ForeName>Melanie</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Human Molecular Genetics and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Froyen</LastName><ForeName>Guy</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Human Genome Laboratory, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ullmann</LastName><ForeName>Reinhard</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Human Molecular Genetics and, Bundeswehr Institute of Radiobiology, 80937 Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hu</LastName><ForeName>Hao</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Human Molecular Genetics and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Love</LastName><ForeName>Michael I</ForeName><Initials>MI</Initials><AffiliationInfo><Affiliation>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haas</LastName><ForeName>Stefan A</ForeName><Initials>SA</Initials><AffiliationInfo><Affiliation>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stankiewicz</LastName><ForeName>Pawel</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cheung</LastName><ForeName>Sau Wai</ForeName><Initials>SW</Initials><AffiliationInfo><Affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baxendale</LastName><ForeName>Anne</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nicholl</LastName><ForeName>Jillian</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thompson</LastName><ForeName>Elizabeth M</ForeName><Initials>EM</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haan</LastName><ForeName>Eric</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kalscheuer</LastName><ForeName>Vera M</ForeName><Initials>VM</Initials><AffiliationInfo><Affiliation>Department of Human Molecular Genetics and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gecz</LastName><ForeName>Jozef</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, jozef.gecz@adelaide.edu.au.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>10</Month><Day>06</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Hum Mol Genet</MedlineTA><NlmUniqueID>9208958</NlmUniqueID><ISSNLinking>0964-6906</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D034961">Antigens, Nuclear</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C508565">STAG2 protein, human</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D034961" MajorTopicYN="N">Antigens, Nuclear</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D041321" MajorTopicYN="N">Chromosomes, Human, X</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D056915" MajorTopicYN="N">DNA Copy Number Variations</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008607" MajorTopicYN="N">Intellectual Disability</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000066553" MajorTopicYN="N">Problem Behavior</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020133" MajorTopicYN="N">Reverse Transcriptase Polymerase Chain Reaction</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>08</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>09</Month><Day>28</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>10</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>10</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>9</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26443594</ArticleId><ArticleId IdType="pii">ddv414</ArticleId><ArticleId 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