ArticleNature communications2023
Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.
Open access · goldAbstract read
In one paragraph
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
3.2field-weighted citation impact, top 8% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
18 citing papers in PubMed, 21 citations in OpenAlex.
- hiPSC-derived Organoids and Organ-on-chip Systems: New Frontiers in Neural Tube Defect Research.Stem cell reviews and reports · 2026Review
- Polycomb Repressive Complex 2 (PRC2): A Context-Dependent Epigenetic Regulator of Brain Aging.Biomolecules · 2026Review
- BiallelicInternational journal of molecular sciences · 2026Article
- From chromatin dynamics to brain disease: Polycomb-Trithorax mechanisms in neurodevelopment.Trends in neurosciences · 2026Review
- Comparative analyses of ChIP-seq, CUT&RUN and CUT&Tag for Polycomb chromatin profiling.BMB reports · 2026Article
- Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder.Brain : a journal of neurology · 2026Article
- GA4GH phenopacket-driven characterization of genotype-phenotype correlations in Mendelian disorders.American journal of human genetics · 2026Article
- Review
- Article
- Cross-species analysis of adult hippocampal neurogenesis reveals human-specific gene expression but convergent biological processes.Nature neuroscience · 2025Article
- Polycomb repressive complexes 1 and 2 independently and dynamically regulate euchromatin during cerebellar neurodevelopment.PLoS genetics · 2025Article
- Loss of DOT1L disrupts neuronal transcription, behavior, and leads to a neurodevelopmental disorder.medRxiv : the preprint server for health sciences · 2025Article
- De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Epigenetics and the timing of neuronal differentiation.Current opinion in neurobiology · 2024Review
- H3K27me3-mediated epigenetic regulation in pluripotency maintenance and lineage differentiation.Cell insight · 2024Review
- Enzyme-independent role of EZH2 in regulating cell cycle progression via the SKP2-KIP/CIP pathway.Scientific reports · 2024Article
- Article
- BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system.The Journal of clinical investigation · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
61 authors at 20 institutions in 9 countries.
Carolina Gracia-DiazRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-1814-2464
Yijing ZhouRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Qian Yang *Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-4005-3580
Reza Maroofian *Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
Paula Espana-Bonilla *Department of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.ORCID http://orcid.org/0000-0002-4691-5607
Chul-Hwan LeeDepartment of Biomedical Sciences and Pharmacology, Seoul National University, College of Medicine, Seoul, South Korea.
Shuo ZhangDepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
Natàlia PadillaResearch Unit in Clinical and Translational Bioinformatics, Vall d'Hebron Institute of Research (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.ORCID http://orcid.org/0000-0002-7872-2279
Raquel FueyoDepartment of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
Elisa A WaxmanRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-4562-7969
Sunyimeng LeiRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Garrett OtrimskiRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Dong LiCenter for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-2265-6727
Sarah E SheppardCenter for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Paul MarkDepartment of Pediatrics, Division of Medical Genetics, Helen DeVos Children's Hospital, Corewell Health, Grand Rapids, MI, USA.ORCID http://orcid.org/0000-0002-1020-888X
Margaret H HarrCenter for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Hakon HakonarsonCenter for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-2814-7461
Lance RodanDepartment of Neurology, Boston Children's Hospital, Boston, MA, USA.
Adam JacksonDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Pradeep VasudevanLeicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, UK.ORCID http://orcid.org/0009-0002-6095-2030
Corrina PowelLeicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, UK.
Shehla MohammedGuy's Hospital, London, UK.
Sateesh MaddirevulaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hamad AlzaidanDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Eissa A FaqeihSection of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
Stephanie EfthymiouDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0000-0003-4900-9877
Valentina TurchettiDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
Fatima RahmanDevelopmental and Behavioral Pediatrics, University of Child Health Sciences & The Children's Hospital, Lahore, Pakistan.
Shazia MaqboolDevelopmental and Behavioral Pediatrics, University of Child Health Sciences & The Children's Hospital, Lahore, Pakistan.
Vincenzo SalpietroDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0000-0003-0132-7921
Shahnaz H IbrahimDepartment of Pediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan.ORCID http://orcid.org/0000-0003-4018-6594
Gabriella di RosaChild Neuropsychiatry Unit, Department of Pediatrics, University of Messina, Messina, 98100, Italy.
Henry HouldenDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0000-0002-2866-7777
Maha Nasser AlharbiMaternity and Children Hospital Buraidah, Qassim Health Cluster, Buraydah, Saudi Arabia.
Nouriya Abbas Al-SannaaJohn Hopkins Aramco Health Care, Pediatric Services, Dhahran, Saudi Arabia.
Peter BauerCentogene GmbH, Rostock, Germany.
Giovanni ZifarelliCentogene GmbH, Rostock, Germany.
Conchi EstarasCenter for Translational Medicine, Department of Cardiovascular Sciences, Temple University, Philadelphia, PA, USA.
Anna C E HurstUniversity of Alabama at Birmingham, Birmingham, AL, USA.ORCID http://orcid.org/0000-0002-9765-9703
Michelle L ThompsonHudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Anna ChasseventDepartment of Neurogenetics, Neurology and Developmental Medicine Kennedy Krieger Institute, Baltimore, MD, USA.
Constance L Smith-HicksDepartment of Neurogenetics, Neurology and Developmental Medicine Kennedy Krieger Institute, Baltimore, MD, USA.
Xavier de la CruzResearch Unit in Clinical and Translational Bioinformatics, Vall d'Hebron Institute of Research (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.
Alexander M HoltzDivision of Genetics & Genomics, Boston Children's Hospital, Boston, MA, USA.
Houda Zghal ElloumiGeneDx, Gaithersburg, MD, 20877, USA.
M J HajianpourDivision of Medical Genetics and Genomics, Department of Pediatrics, Albany Medical College, Albany, NY, USA.
Claudine RieublandDepartment of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Dominique BraunDepartment of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.ORCID http://orcid.org/0000-0002-4340-4334
Siddharth BankaDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID http://orcid.org/0000-0002-8527-2210
Genomic England Research Consortium
Deborah L FrenchRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Elizabeth A HellerDepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-2984-8705
Murielle SaadeDepartment of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
Hongjun SongDepartment of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-8720-5310
Guo-Li MingDepartment of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-2517-6075
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.ORCID http://orcid.org/0000-0003-4158-341X
Pankaj B AgrawalDivision of Genetics & Genomics, Boston Children's Hospital, Boston, MA, USA.
Danny ReinbergHHMI/NYU Langone School of Medicine, New York, NY, USA.
Elizabeth J BhojRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Marian A Martínez-BalbásDepartment of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.ORCID http://orcid.org/0000-0003-0173-0964
Naiara AkizuRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. aquizun@chop.edu.ORCID http://orcid.org/0000-0001-9222-6960
Genomics England · GBQueen Mary University of London · GBChildren's Hospital of Philadelphia · USNational Hospital for Neurology and Neurosurgery · GBConsejo Superior de Investigaciones Científicas · ESBoston Children's Hospital · USUniversity of Pennsylvania · USCentogene (Germany) · DEKennedy Krieger Institute · USKing Faisal Specialist Hospital & Research Centre · SALeicester Royal Infirmary · GBTranslational Therapeutics (United States) · USUniversity of Bern · CHUniversity of Health Sciences Lahore · PKUniversity of Manchester · GBAga Khan University Hospital · PKAlbany Medical Center Hospital · USAlfaisal University · SABuraydah Colleges · SAGuy's Hospital · GB
Funding
Sleep and Circadian Dysfunction, Brain and Neurobehavioral Development in AutismP50HD103538 · NICHD · HUGO W. MOSER RES INST KENNEDY KRIEGER · PI S. Ali Fatemi, Bradley L Schlaggar · 2020 to 2026
$9.9MContinuous Neurogenesis in the Mammalian HippocampusR35NS116843 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI HONGJUN SONG · 2020 to 2026
$6.9MFunctional roles of genetic risk factors for brain disorders in neurogenesis and neurodevelopmentR35NS097370 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI MING, GUO-LI · 2017 to 2024
$6.7MThe role of EZH1 in neuronal differentiation and neurological disordersR01NS119699 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI Naiara Akizu · 2022 to 2026
$2.8MSliced human neocortical organoids for modeling cortical laminar and columnar organization and functionRF1MH123979 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI MING, GUO-LI · 2020 to 2020
$1.7MLeveraging a newly identified EZH1 associated syndrome to explore pharmacological recovery of neurodevelopmental disordersR21HD107592 · NICHD · CHILDREN'S HOSP OF PHILADELPHIA · PI AKIZU, NAIARA · 2022 to 2023
$509kMedical Research Council MR/S006753/1NICHD NIH HHS P50 HD103538NICHD NIH HHS R21 HD107592NIMH NIH HHS RF1 MH123979NINDS NIH HHS R01 NS119699NINDS NIH HHS R35 NS097370NINDS NIH HHS R35 NS116843Wellcome TrustWellcome Trust WT098051
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.
Indexed as
Neurodevelopmental DisordersNeurogenesisPolycomb Repressive Complex 2AnimalsCell DifferentiationCell NucleusChick EmbryoChromatinHumansMethyltransferasesChromatinEZH1 protein, humanMethyltransferasesPolycomb Repressive Complex 2
Identifiers
What OpenQuestion holds
Textmetadata
LicenceCC BY
Read underepoch 390
Registered trials
None linked
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.