Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders
Authors: Gracia-Diaz Carolina , Zhou Yijing , Yang Qian , Maroofian Reza , Espana-Bonilla Paula , Lee Chul-Hwan , Zhang Shuo , Padilla Natàlia , Fueyo Raquel , Waxman Elisa A. , Lei Sunyimeng , Otrimski Garrett , Li Dong , Sheppard Sarah E. , Mark Paul , Harr Margaret H. , Hakonarson Hakon , Rodan Lance , Jackson Adam , Vasudevan Pradeep , Powel Corrina , Mohammed Shehla , Maddirevula Sateesh , Alzaidan Hamad , Faqeih Eissa A. , Efthymiou Stephanie , Turchetti Valentina , Rahman Fatima , Maqbool Shazia , Salpietro Vincenzo , Ibrahim Shahnaz H. , di Rosa Gabriella , Houlden Henry , Alharbi Maha Nasser , Al-Sannaa Nouriya Abbas , Bauer Peter , Zifarelli Giovanni , Estaras Conchi , Hurst Anna C. E. , Thompson Michelle L. , Chassevent Anna , Smith-Hicks Constance L. , de la Cruz Xavier , Holtz Alexander M. , Elloumi Houda Zghal , Hajianpour M J , Rieubland Claudine , Braun Dominique , Banka Siddharth ,   Genomic England Research Consortium, Ambrose J. C. , Arumugam P. , Bevers R. , Bleda M. , Boardman-Pretty F. , Boustred C. R. , Brittain H. , Brown M. A. , Caulfield M. J. , Chan G. C. , Giess A. , Griffin J. N. , Hamblin A. , Henderson S. , Hubbard T. J. P. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Kousathanas A. , Lahnstein L. , Lakey A. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , McEntagart M. , Minneci F. , Mitchell J. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , O’Donovan P. , Odhams C. A. , Patch C. , Perez-Gil D. , Pereira M. B. , Pullinger J. , Rahim T. , Rendon A. , Rogers T. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smith S. C. , Sosinsky A. , Stuckey A. , Tanguy M. , Taylor Tavares A. L. , Thomas E. R. A. , Thompson S. R. , Tucci A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Zarowiecki M. , French Deborah L. , Heller Elizabeth A. , Saade Murielle , Song Hongjun , Ming Guo-li , Alkuraya Fowzan S. , Agrawal Pankaj B. , Reinberg Danny , Bhoj Elizabeth J. , Martínez-Balbás Marian A. , Akizu Naiara 
Published: July 2023

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifierEZH1as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals.EZH1encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impairEZH1expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of twoEZH1missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate thatEZH1variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.