Gabriele, M.Vulto-van Silfhout, A.Germain, P.Vitriolo, A.Kumar, R.Douglas, E.Haan, E.Kosaki, K.Takenouchi, T.Rauch, A.Steindl, K.Frengen, E.Misceo, D.Pedurupillay, C.Stromme, P.Rosenfeld, J.Shao, Y.Craigen, W.Schaaf, C.Rodriguez-Buritica, D.et al.2017-06-252017-06-252017American Journal of Human Genetics, 2017; 100(6):907-9250002-92971537-6605http://hdl.handle.net/2440/106217Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.en© 2017 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).H3K27AcYY1chromatinenhancerepigeneticshaploinsufficiencyintellectual disabilityneurodevelopmentsyndrometranscription factorYY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunctionJournal article003007091410.1016/j.ajhg.2017.05.0060004027006000072-s2.0-85020105976355817Kumar, R. [0000-0001-7976-8386]Haan, E. [0000-0002-7310-5124]Anderson, P. [0000-0002-3730-4652]Gecz, J. [0000-0002-7884-6861]