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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.

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