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Hum Mol Genet. 2015 Dec 20;24(25):7171-81. doi: 10.1093/hmg/ddv414. Epub 2015 Oct 6.

Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.

Author information

1
School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
2
Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
3
Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
4
Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
5
Centre Hospitalier Régional Universitaire, Service de Génétique, 37000 Tours, France.
6
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
7
Department of Endocrinology, Metabolism and Internal Diseases and.
8
Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-355, Poland.
9
Department of Pediatrics, Saint Louis University, St Louis, MO 63104, USA.
10
Signature Genomic Laboratories, Spokane, WA 99207, USA, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
11
Raphael Recanati Genetic Institute and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.
12
Department of Human Molecular Genetics and.
13
Human Genome Laboratory, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium and.
14
Department of Human Molecular Genetics and, Bundeswehr Institute of Radiobiology, 80937 Munich, Germany.
15
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
16
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
17
South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.
18
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.
19
School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia, jozef.gecz@adelaide.edu.au.

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.

PMID:
26443594
DOI:
10.1093/hmg/ddv414
[Indexed for MEDLINE]

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