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

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, Bartlomiej Budny, Marzena Wisniewska, Magdalena Badura-Stronka, Anna Latos-Bieleńska, Jacqueline Batanian, Jill A. RosenfeldLina 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 Gecz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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.

Original languageEnglish
Pages (from-to)7171-7181
Number of pages11
JournalHuman Molecular Genetics
Issue number25
StatePublished - 20 Dec 2015
Externally publishedYes


FundersFunder number
Channel 7 Children''s Research Foundation
EU FP7241995
WCH Foundation
National Health and Medical Research Council1041920, 628952


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