Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Carolina Gracia-Diaz, Yijing Zhou, Qian Yang, Reza Maroofian, Paula Espana-Bonilla, Chul-Hwan Lee, Shuo Zhang, Natàlia Padilla, Raquel Fueyo, Elisa A. Waxman, Sunyimeng Lei, Garrett Otrimski, Dong Li, Sarah E. Sheppard, Paul Mark, Margaret H. Harr, Hakon Hakonarson, Lance Rodan, Adam Jackson, Pradeep Vasudevan, Corrina Powel, Shehla Mohammed, Sateesh Maddirevula, Hamad Alzaidan, Eissa A. Faqeih, Stephanie Efthymiou, Valentina Turchetti, Fatima Rahman, Shazia Maqbool, Vincenzo Salpietro, Shahnaz H. Ibrahim, Gabriella Rosa, Henry Houlden, Maha Nasser Alharbi, Nouriya Abbas Al-Sannaa, Peter Bauer, Giovanni Zifarelli, Conchi Estaras, Anna C. E. Hurst, Michelle L. Thompson, Anna Chassevent, Constance L. Smith-Hicks, Xavier Cruz, Alexander M. Holtz, Houda Zghal Elloumi, M J Hajianpour, Claudine Rieubland, Dominique Braun, Siddharth Banka, Deborah L. French, Elizabeth A. Heller, Murielle Saade, Hongjun Song, Guo-li Ming, Fowzan S. Alkuraya, Pankaj B. Agrawal, Danny Reinberg, Elizabeth J. Bhoj, Marian A. Martínez-Balbás and Naiara Akizu ()
Additional contact information
Carolina Gracia-Diaz: The Children’s Hospital of Philadelphia
Yijing Zhou: The Children’s Hospital of Philadelphia
Qian Yang: University of Pennsylvania
Reza Maroofian: University College London
Paula Espana-Bonilla: Consejo Superior de Investigaciones Científicas (CSIC)
Chul-Hwan Lee: Seoul National University, College of Medicine
Shuo Zhang: University of Pennsylvania
Natàlia Padilla: Universitat Autonoma de Barcelona
Raquel Fueyo: Consejo Superior de Investigaciones Científicas (CSIC)
Elisa A. Waxman: The Children’s Hospital of Philadelphia
Sunyimeng Lei: The Children’s Hospital of Philadelphia
Garrett Otrimski: The Children’s Hospital of Philadelphia
Dong Li: The Children’s Hospital of Philadelphia
Sarah E. Sheppard: The Children’s Hospital of Philadelphia
Paul Mark: Helen DeVos Children’s Hospital, Corewell Health
Margaret H. Harr: The Children’s Hospital of Philadelphia
Hakon Hakonarson: The Children’s Hospital of Philadelphia
Lance Rodan: Boston Children’s Hospital
Adam Jackson: Medicine and Health, University of Manchester
Pradeep Vasudevan: University Hospitals of Leicester NHS Trust
Corrina Powel: University Hospitals of Leicester NHS Trust
Shehla Mohammed: Guy’s Hospital
Sateesh Maddirevula: Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Hamad Alzaidan: King Faisal Specialist Hospital and Research Center
Eissa A. Faqeih: Children’s Specialist Hospital
Stephanie Efthymiou: University College London
Valentina Turchetti: University College London
Fatima Rahman: University of Child Health Sciences & The Children’s Hospital
Shazia Maqbool: University of Child Health Sciences & The Children’s Hospital
Vincenzo Salpietro: University College London
Shahnaz H. Ibrahim: Department of Pediatrics and Child Health, Aga Khan University Hospital
Gabriella Rosa: University of Messina
Henry Houlden: University College London
Maha Nasser Alharbi: Qassim Health Cluster
Nouriya Abbas Al-Sannaa: John Hopkins Aramco Health Care, Pediatric Services
Peter Bauer: Centogene GmbH
Giovanni Zifarelli: Centogene GmbH
Conchi Estaras: Temple University
Anna C. E. Hurst: University of Alabama at Birmingham
Michelle L. Thompson: HudsonAlpha Institute for Biotechnology
Anna Chassevent: Neurology and Developmental Medicine Kennedy Krieger Institute
Constance L. Smith-Hicks: Neurology and Developmental Medicine Kennedy Krieger Institute
Xavier Cruz: Universitat Autonoma de Barcelona
Alexander M. Holtz: Boston Children’s Hospital
Houda Zghal Elloumi: GeneDx
M J Hajianpour: Albany Medical College
Claudine Rieubland: Inselspital, Bern University Hospital, University of Bern
Dominique Braun: Inselspital, Bern University Hospital, University of Bern
Siddharth Banka: Medicine and Health, University of Manchester
Deborah L. French: The Children’s Hospital of Philadelphia
Elizabeth A. Heller: University of Pennsylvania
Murielle Saade: Consejo Superior de Investigaciones Científicas (CSIC)
Hongjun Song: University of Pennsylvania
Guo-li Ming: University of Pennsylvania
Fowzan S. Alkuraya: Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Pankaj B. Agrawal: Boston Children’s Hospital
Danny Reinberg: HHMI/NYU Langone School of Medicine
Elizabeth J. Bhoj: The Children’s Hospital of Philadelphia
Marian A. Martínez-Balbás: Consejo Superior de Investigaciones Científicas (CSIC)
Naiara Akizu: The Children’s Hospital of Philadelphia

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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 modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes 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 impair EZH1 expression 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 two EZH1 missense 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 that EZH1 variants 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.

Date: 2023
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DOI: 10.1038/s41467-023-39645-5

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