ArticleAmerican journal of human genetics2019
Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.
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Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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51 citing papers in PubMed, 98 citations in OpenAlex.
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- Clinical immunology in chromatinopathies: a scoping review.Frontiers in immunology · 2026Article
- Common and rare genetic variants explain distinct diagnostic variance in pediatric attention deficit hyperactivity disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Autism Spectrum Disorder: The Cerebellum, Genes, and Pathways.Neurology international · 2025Review
- Transcriptomic Convergence and the Female Protective Effect in Autism.bioRxiv : the preprint server for biology · 2025Article
- Evaluation of familial phenotype deviation to measure the impact of de novo mutations in autism.Genome medicine · 2025Article
- Exploring the bidirectional causal relationship between Autism Spectrum Disorder and Schizophrenia using Mendelian randomization.Medicine · 2025Article
- Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders.iScience · 2025Review
- Mechanisms of brain overgrowth in autism spectrum disorder with macrocephaly.Frontiers in neuroscience · 2025Review
- Human-specific insights into candidate genes and boosted discoveries of novel loci illuminate roles of neuroglia in reading disorders.Genes, brain, and behavior · 2024Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.Genome medicine · 2024Article
- Clinical and genetic analysis of a case of OZhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2024Article
- Defining Biological and Biochemical Functions of Noncanonical SET Domain Proteins.Journal of molecular biology · 2024Review
- Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.medRxiv : the preprint server for health sciences · 2024Article
- Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments.Human mutation · 2024Review
- Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain.Nature genetics · 2023Article
- Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.Genome medicine · 2023Article
- Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.Human molecular genetics · 2023Review
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Authors and funding
86 authors at 20 institutions in 14 countries.
Anne H O'Donnell-LuriaDivision of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: Anne.ODonnell@childrens.harvard.edu.
Lynn S PaisBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Víctor FaundesDivision of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago, Chile.
Jordan C WoodBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Abigail SvedenBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Victor LuriaDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany.
Andrea AccogliDepartment of Pediatrics, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Quebec, Canada; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica Scienze Materno-Infantili, Università degli studi di Genova, 16126 Genova, Italy; IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
Kimberly AmburgeyDivision of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, ON, Canada.
Britt Marie AnderlidDepartment of Molecular Medicine and Surgery, Centre for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm 17176, Sweden.
Silvia Azzarello-BurriInstitute of Medical Genetics, University of Zurich, Schlieren-Zurich CH-8952, Switzerland; Neuroscience Center Zurich, University of Zurich and Eidgenössische Technische Hochschule, Zurich 8057, Switzerland.
Alice A BasingerGenetics, Cook Children's Physician Network, Fort Worth, TX 76104, USA.
Claudia BianchiniPediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, University of Florence, 50139 Florence, Italy.
Lynne M BirdDepartment of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Division of Genetics, Rady Children's Hospital of San Diego, San Diego, CA 92123, USA.
Rebecca BuchertInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
Wilfrid CarreLaboratoire de Génétique Moléculaire et Génomique, Centre Hospitalier Universitaire de Rennes, Rennes 35033, France.
Sophia CeulemansDivision of Genetics, Rady Children's Hospital of San Diego, San Diego, CA 92123, USA.
Perrine CharlesDepartment of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France; Groupe de Recherche Clinique Déficience Intellectuelle et Autisme, Sorbonne University, Paris 75006, France.
Helen CoxWest Midlands Regional Clinical Genetics Service, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham B15 2TG, UK; Birmingham Health Partners, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham B15 2TG, UK.
Lisa CullitonDepartment of Neurology, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA.
Aurora CurròMedical Genetics, University of Siena, 53100 Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.
Deciphering Developmental Disorders (DDD) StudyWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
Florence DemurgerService de Génétique Clinique, Centre de Référence Maladies Rares Centre Labellisé Anomalies du Développement-Ouest, Centre Hospitalier Universitaire de Rennes, 35033 Rennes, France.
James J DowlingDivision of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, ON, Canada.
Benedicte Duban-BeduCentre de Génétique Chromosomique, Groupement des Hôpitaux de l'Institut Catholique de Lille Hôpital Saint Vincent de Paul, 59020 Lille, France; Faculté de médecine de l'Université Catholoique de Lille, 59800 Lille, France.
Christèle DubourgLaboratoire de Génétique Moléculaire et Génomique, Centre Hospitalier Universitaire de Rennes, Rennes 35033, France.
Saga Elise EisetDepartment of Clinical Genetics, Aarhus University Hospital, 8200 Aarhus, Denmark.
Luis F EscobarSt. Vincent's Children's Hospital, Indianapolis, IN 46260, USA.
Alessandra FerrariniMedical Genetic Unit, Italian Hospital of Lugano, Lugano, Switzerland; Università della Svizzera Italiana, 6900 Lugano, Switzerland.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
Mona HashimOxford National Institute for Health Research Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Solveig HeideDepartment of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France; Groupe de Recherche Clinique Déficience Intellectuelle et Autisme, Sorbonne University, Paris 75006, France.
Katherine L HelbigDivision of Neurology and Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Ingo HelbigDivision of Neurology and Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104 USA; Department of Neuropediatrics, University Medical Center, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
Raul HerediaGeneDx, Gaithersburg, MD 20877, USA.
Delphine HéronDepartment of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France; Groupe de Recherche Clinique Déficience Intellectuelle et Autisme, Sorbonne University, Paris 75006, France.
Bertrand IsidorService de Génétique Médicale, Hôpital Hôtel-Dieu, Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France.
Amy R JonassonDivision of Genetics and Metabolism, Department of Pediatrics, University of Florida, FL 32610, USA.
Pascal JosetInstitute of Medical Genetics, University of Zurich, Schlieren-Zurich CH-8952, Switzerland; Neuroscience Center Zurich, University of Zurich and Eidgenössische Technische Hochschule, Zurich 8057, Switzerland.
Boris KerenDepartment of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France; Groupe de Recherche Clinique Déficience Intellectuelle et Autisme, Sorbonne University, Paris 75006, France.
Fernando KokMendelics Genomic Analysis, Sao Paulo 04013, Brazil.
Hester Y KroesDepartment of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
Alinoë LavillaureixService de Génétique Clinique, Centre de Référence Maladies Rares Centre Labellisé Anomalies du Développement-Ouest, Centre Hospitalier Universitaire de Rennes, 35033 Rennes, France.
Xin LuLudwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
Saskia M MaasDepartment of Clinical Genetics, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Gustavo H B MaegawaDivision of Genetics and Metabolism, Department of Pediatrics, University of Florida, FL 32610, USA.
Carlo L M MarcelisDepartment of Clinical Genetics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Paul R MarkDivision of Medical Genetics and Genomics, Spectrum Health, Grand Rapids, MI 49544, USA.
Marcelo R MasruhaDepartment of Neurology and Neurosurgery, Universidade de Federal de São Paulo, São Paulo 04023, Brazil.
Heather M McLaughlinGeneDx, Gaithersburg, MD 20877, USA.
Kirsty McWalterGeneDx, Gaithersburg, MD 20877, USA.
Esther U MelchingerInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
Saadet Mercimek-AndrewsDivision of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
Caroline NavaDepartment of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France; Groupe de Recherche Clinique Déficience Intellectuelle et Autisme, Sorbonne University, Paris 75006, France.
Manuela PendziwiatDepartment of Neuropediatrics, University Medical Center, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
Richard PersonGeneDx, Gaithersburg, MD 20877, USA.
Gian Paolo RamelliNeuropediatric Unit, Pediatric Department of Southern Switzerland, San Giovanni Hospital, 6500 Bellinzona, Switzerland.
Luiza L P RamosMendelics Genomic Analysis, Sao Paulo 04013, Brazil.
Anita RauchInstitute of Medical Genetics, University of Zurich, Schlieren-Zurich CH-8952, Switzerland; Neuroscience Center Zurich, University of Zurich and Eidgenössische Technische Hochschule, Zurich 8057, Switzerland; Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, CH-8006 Zurich, Switzerland.
Caitlin ReaveyGeneDx, Gaithersburg, MD 20877, USA.
Alessandra RenieriMedical Genetics, University of Siena, 53100 Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.
Angelika RießInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
Amarilis Sanchez-ValleDepartment of Pediatrics, Division of Genetics and Metabolism, University of South Florida, Tampa, FL 33606, USA.
Shifteh SattarSection of Pediatric Neurology, Rady Children's Hospital, San Diego, CA 92123, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
Carol SaundersCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA; School of Medicine, University of Missouri, Kansas City, MO 64108, USA.
Niklas SchwarzDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
Thomas SmolEA7364 Rares du Developpement Embryonnaire et du Metabolisme, Institut de Genetique Medicale, Centre Hospitalier Universitaire de Lille, University of Lille, F-59000 Lille, France.
Myriam SrourDepartment of Pediatrics, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Quebec, Canada.
Katharina SteindlInstitute of Medical Genetics, University of Zurich, Schlieren-Zurich CH-8952, Switzerland; Neuroscience Center Zurich, University of Zurich and Eidgenössische Technische Hochschule, Zurich 8057, Switzerland.
Steffen SyrbeDivision of Child Neurology and Inherited Metabolic Diseases, Department of General Paediatrics, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Jenny C TaylorOxford National Institute for Health Research Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Aida TelegrafiGeneDx, Gaithersburg, MD 20877, USA.
Isabelle ThiffaultSchool of Medicine, University of Missouri, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA.
Doris A TraunerSection of Pediatric Neurology, Rady Children's Hospital, San Diego, CA 92123, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
Helio van der LindenPediatric Neurology and Neurophysiology, Instituto de Neurologia de Goiania, Goiania 74210, Brazil.
Silvana van KoningsbruggenDepartment of Clinical Genetics, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Laurent VillardDepartment of Medical Genetics, Assistance Publique - Hôpitaux de Marseille, Hôpital d'Enfants de La Timone, 13005 Marseille, France; Marseille Medical Genetics Center, Aix Marseille Univ, Inserm, U1251, Marseille, France.
Ida VogelDepartment of Clinical Genetics, Aarhus University Hospital, 8200 Aarhus, Denmark; Center for Fetal Diagnostics, Aarhus University Hospital, 8200 Aarhus, Denmark.
Julie VogtWest Midlands Regional Clinical Genetics Service, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham B15 2TG, UK; Birmingham Health Partners, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham B15 2TG, UK.
Yvonne G WeberDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; Department for Neurosurgery, University of Tübingen, 72076 Tübingen, Germany.
Ingrid M WentzensenGeneDx, Gaithersburg, MD 20877, USA.
Elysa WidjajaDepartment of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, ON, Canada.
Jaroslav ZakLudwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Samantha BaxterBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Siddharth BankaDivision of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University National Health Service Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
Lance H RodanDivision of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Lance.Rodan@childrens.harvard.edu.
Wessex Regional Genetics Laboratory · GBUniversity of Tübingen · DEAmgen (United Kingdom) · GBUniversity of Oxford · GBChildren's Mercy Hospital · USMassachusetts Institute of Technology · USOur Lady's Hospital · IEPitié-Salpêtrière Hospital · FRBroad Institute · USCentre Hospitalier Universitaire de Rennes · FRHospital for Sick Children · CAMcGill University · CASheffield Children's NHS Foundation Trust · GBSpectrum Health · USUniversity of Birmingham · GBUniversity of California, San Diego · USWellcome Sanger Institute · GBAssistance Publique – Hôpitaux de Paris · FRBirmingham Women’s and Children’s NHS Foundation Trust · GBBoston Children's Hospital · US
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MThe Child Heath Research CenterK12HD052896 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI Wendy K Chung · 2007 to 2026
$7.9MSystems Analysis of cell type differentiation in Xenopus developmentR01HD073104 · NICHD · HARVARD MEDICAL SCHOOL · PI KIRSCHNER, MARC WALLACE, PESHKIN, LEON · 2012 to 2022
$6.7MProteomics of Cell Signaling in Embryogenesis.R01HD091846 · NICHD · HARVARD MEDICAL SCHOOL · PI GYGI, STEVEN P, KIRSCHNER, MARC WALLACE · 2017 to 2021
$3.1MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MMedical Research Council MC_PC_16018NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900NICHD NIH HHS K12 HD052896NICHD NIH HHS R01 HD073104NICHD NIH HHS R01 HD091846Wellcome Trust WT098051
Abstract
We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Indexed as
Genetic VariationHeterozygoteAdolescentAdultChildChild, PreschoolDNA-Binding ProteinsEpilepsyFemaleHaploinsufficiencyHumansInfantMaleNeurodevelopmental DisordersPedigreePhenotypeDNA-Binding ProteinsKMT2E protein, humanautismepilepsyepileptic encephalopathyglobal developmental delayH3K4 methylationintellectual disabilityKMT2Eneurodevelopmental disorder
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