title: Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.
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.
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Corbett
authors.affiliation: Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: Van Bon
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Alison
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authors.lastname: Gardner
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Woenig
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Lachlan A
authors.initials: LA
authors.lastname: Jolly
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Evelyn
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authors.lastname: Douglas
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Friend
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Chuan
authors.initials: C
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authors.affiliation: Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Maureen
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authors.lastname: Holvoet
authors.affiliation: Centre Hospitalier Régional Universitaire, Service de Génétique, 37000 Tours, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Michael
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authors.lastname: Field
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
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authors.affiliation: Department of Endocrinology, Metabolism and Internal Diseases and.
authors.forename: Bartłomiej
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authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.
authors.forename: Marzena
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authors.lastname: Wisniewska
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.
authors.forename: Magdalena
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authors.lastname: Badura-Stronka
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.
authors.forename: Anna
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authors.lastname: Latos-Bieleńska
authors.affiliation: Department of Pediatrics, Saint Louis University, St Louis, MO 63104, USA.
authors.forename: Jacqueline
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authors.lastname: Batanian
authors.affiliation: Signature Genomic Laboratories, Spokane, WA 99207, USA, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Raphael Recanati Genetic Institute and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.affiliation: Department of Human Molecular Genetics and.
authors.forename: Corinna
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authors.lastname: Jensen
authors.affiliation: Department of Human Molecular Genetics and.
authors.forename: Melanie
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authors.lastname: Bienek
authors.affiliation: Human Genome Laboratory, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium and.
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
authors.affiliation: Department of Human Molecular Genetics and, Bundeswehr Institute of Radiobiology, 80937 Munich, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.affiliation: Department of Human Molecular Genetics and.
authors.forename: Hao
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authors.lastname: Hu
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Love
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Baxendale
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Jillian
authors.initials: J
authors.lastname: Nicholl
authors.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.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Thompson
authors.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.
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.affiliation: Department of Human Molecular Genetics and.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, jozef.gecz@adelaide.edu.au.
authors.forename: Jozef
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mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics*; D018797:Cell Cycle Proteins; D041321:Chromosomes, Human, X / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D000066553:Problem Behavior; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; C508565:STAG2 protein, human; D000097722:Cohesins