ArticleAmerican journal of human genetics2023
The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.
Erratum issuedOpen access · greenAbstract read
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Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 20 papers.
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20citing papers in PubMed
9.1field-weighted citation impact, top 2% of its field
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- Epigenetic Activation of the KDM6B-DKK1 Axis Promotes Colorectal Cancer Peritoneal Metastasis Through Wnt/β-Catenin-Associated EMT.Journal of cellular and molecular medicine · 2026Article
- Further characterization of the BRSK2-associated neurodevelopmental disorder.European journal of human genetics : EJHG · 2026Article
- Kdm6b-mediated epigenetic coordination of temporal precision during motor neuron differentiation.EMBO reports · 2026Article
- hsa_circ_0006168 drives microglial activation in TNC via miR-99b-5p/KDM6B axis to promote central sensitization in migraine.The journal of headache and pain · 2026Article
- De novo variants in KDM2A cause a syndromic neurodevelopmental disorder.American journal of human genetics · 2026Article
- Histone demethylase KDM6B promotes postnatal oligodendrocyte maturation and cortical myelination.Frontiers in cellular neuroscience · 2026Article
- NovelNeurology. Genetics · 2025Article
- Sex-Dependent Phenotypic and Histomorphometric Biomarkers in the APPswe/PS1dE9/Blg Mouse Model of Alzheimer's Disease.Brain sciences · 2025Article
- Polycomb-associated and Trithorax-associated developmental conditions-phenotypic convergence and heterogeneity.European journal of human genetics : EJHG · 2025Article
- Functional assays inGenome research · 2025Review
- Neuroradiologic, Clinical, and Genetic Characterization of Cerebellar Heterotopia: A Pediatric Multicentric Study.AJNR. American journal of neuroradiology · 2025Article
- Chromatin modifiers in neurodevelopment.Frontiers in molecular neuroscience · 2025Review
- Mechanisms of brain overgrowth in autism spectrum disorder with macrocephaly.Frontiers in neuroscience · 2025Review
- Genetic Heterogeneity in Four Probands RevealsBiomedicines · 2024Article
- Genome Sequencing Identifies 13 Novel Candidate Risk Genes for Autism Spectrum Disorder in a Qatari Cohort.International journal of molecular sciences · 2024Article
- Understanding the Role of the SMN Complex Component GEMIN5 and Its Functional Relationship with Demethylase KDM6B in the Flunarizine-Mediated Neuroprotection of Motor Neuron Disease Spinal Muscular Atrophy.International journal of molecular sciences · 2024Article
- Impact of KDM6B mosaic brain knockout on synaptic function and behavior.Scientific reports · 2024Article
- Neurodevelopmental functions of CHD8: new insights and questions.Biochemical Society transactions · 2024Review
- Understanding GEMIN5 Interactions: From Structural and Functional Insights to Selective Translation.Wiley interdisciplinary reviews. RNAReview
Corrections and comments
- Erratum issued
Authors and funding
118 authors at 20 institutions in 14 countries.
Dmitrijs RotsRadboudumc, Department of Human Genetics, Nijmegen, the Netherlands.
Taryn E JakubDalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada.
Crystal KeungDalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada.
Adam JacksonDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Siddharth BankaDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Rolph PfundtRadboudumc, Department of Human Genetics, Nijmegen, the Netherlands.
Bert B A de VriesRadboudumc, Department of Human Genetics, Nijmegen, the Netherlands.
Richard H van JaarsveldDepartment of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Saskia M J HopmanDepartment of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Ellen van BinsbergenDepartment of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Irene ValenzuelaHospital Universitari Vall D'Hebron, Clinical and Molecular Genetics Unit, Barcelona, Catalonia, Spain.
Maja HempelInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Tatjana BierhalsInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Fanny KortümInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Francois LecoquierreUniversity Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France.
Alice GoldenbergUniversity Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France.
Jens Michael HertzOdense University Hospital, Department of Clinical Genetics, Odense, Denmark; University of Southern Denmark, Department of Clinical Research, Odense, Denmark.
Charlotte Brasch AndersenOdense University Hospital, Department of Clinical Genetics, Odense, Denmark.
Maria KibækDepartment of Pediatrics, Odense University Hospital, Odense, Denmark.
Eloise J PrijolesGreenwood Genetic Center, Greenwood, SC, USA.
Roger E StevensonGreenwood Genetic Center, Greenwood, SC, USA.
David B EvermanGreenwood Genetic Center, Greenwood, SC, USA.
Wesley G PattersonGreenwood Genetic Center, Greenwood, SC, USA.
Linyan MengDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77021, USA.
Charul GijavanekarDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77021, USA.
Karl De DiosDivision of Medical Genetics, Dayton Children's Hospital, Dayton, OH, USA.
Shenela LakhaniCenter for Neurogenetics, Weill Cornell Medicine, Brain and Mind Research Institute, New York, NY, USA.
Tess LevyCenter for Neurogenetics, Weill Cornell Medicine, Brain and Mind Research Institute, New York, NY, USA.
Matias WagnerInstitute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany; Division of Pediatric Neurology, Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, Munich, Germany.
Dagmar WieczorekInstitute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Paul J BenkeDivision of Genetics, Joe DiMaggio Children's Hospital, Hollywood, FL, USA.
María Soledad Lopez GarciaHospital Universitario Donostia, San Sebastián, Spain.
Renee PerrierDepartment of Medical Genetics, Alberta Children's Hospital and Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Sergio B SousaMedical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
Pedro M AlmeidaMedical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
Maria José SimõesCBR Genomics, Cantanhede, Portugal; Genoinseq, Next-Generation Sequencing Unit, Biocant, Cantanhede, Portugal.
Bertrand IsidorService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Wallid DebService de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
Andrew A SchmanskiDepartment of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA.
Omar Abdul-RahmanDepartment of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA.
Christophe PhilippeUnité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France.
Ange-Line BruelUnité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France.
Laurence FaivreInserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France; Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs", Centre de Génétique, FHU-TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France.
Antonio VitobelloUnité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France.
Christel ThauvinUnité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
Jeroen J SmitsRadboudumc, Department of Human Genetics, Nijmegen, the Netherlands.
Livia GaravelliMedical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.
Stefano G CaraffiMedical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.
Francesca PelusoMedical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.
Laura Davis-KeppenUniversity of South Dakota Sanford School of Medicine and Sanford Children's Hospital, Sioux Falls, SD, USA.
Dylan PlattUniversity of South Dakota Sanford School of Medicine and Sanford Children's Hospital, Sioux Falls, SD, USA.
Erin RoyerUniversity of South Dakota Sanford School of Medicine and Sanford Children's Hospital, Sioux Falls, SD, USA.
Lisette LeeuwenUniversity Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
Margje SinnemaMaastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands.
Alexander P A StegmannMaastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands.
Constance T R M StumpelMaastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands; Department of Clinical Genetics and GROW-School for Oncology and Reproduction, Maastricht, the Netherlands.
George E TillerKaiser Permanente, Department of Genetics, Los Angeles, CA, USA.
Daniëlle G M BoschErasmus Medical Centre, Genetics Department, Rotterdam, the Netherlands.
Stephanus T PotgieterLaurentius Hospital, Roermond, the Netherlands.
Shelagh JossWest of Scotland Regional Genetics Service, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow, UK.
Miranda SplittNorthern Genetics Service, Institute of Genetic Medicine, International Centre for Life, Newcastle Upon Tyne NE1 3BZ, UK.
Simon HoldenDepartment of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.
Matina PrapaDepartment of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.
Nicola FouldsWessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK.
Sofia DouzgouDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
Kaija PuuraDepartment of Child Psychiatry, Tampere University and Tampere University Hospital, Tampere, Finland.
Regina WaltesDepartment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe-Universität, Frankfurt am Main, Germany.
Andreas G ChiocchettiDepartment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe-Universität, Frankfurt am Main, Germany.
Christine M FreitagDepartment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe-Universität, Frankfurt am Main, Germany.
F Kyle SatterstromAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Silvia De RubeisMindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Joseph BuxbaumMindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bruce D GelbMindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Aleksic BrankoDepartment of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Itaru KushimaDepartment of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan; Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan.
Jennifer HoweThe Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
Stephen W SchererThe Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
Alessia AradoLaboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Chiara BaldoLaboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Olivier PatatService de Génétique Médicale, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
Demeer BénédicteService de Génétique Clinique, Centre de référence maladies rares, CHU d'Amiens-site Sud, Amiens, France.
Diego LopergoloDepartment of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero Universitaria Senese, Policlinico Le Scotte, Viale Bracci, 2, 53100 Siena, Italy; IRCCS Stella Maris Foundation, Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, Pisa, Italy.
Filippo M SantorelliIRCCS Stella Maris Foundation, Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, Pisa, Italy.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Andreas DufkeInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Miriam BertrandInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Ruth J FalbInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Angelika RießInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Peter KriegDepartment of Pediatrics, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
Stephanie SprangerPractice of Human Genetics, Bremen, Germany.
Maria Francesca BedeschiMedical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
Maria IasconeLaboratory of Medical Genetics, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
Sarah Josephi-TaylorDepartment of Clinical Genetics, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
Tony RoscioliNeuroscience Research Australia, University of New South Wales, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics Laboratory, Sydney, NSW, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW 2031, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2031, Australia.
Michael F BuckleyNew South Wales Health Pathology Randwick Genomics Laboratory, Sydney, NSW, Australia.
Jan LiebeltSouth Australian Clinical Genetics Service, Women's and Children's Hospital, Adelaide, SA, Australia.
Aditi I DagliOrlando Health Arnold Palmer Hospital for Children, Division of Genetics, Orlando, FL, USA.
Emmelien AtenDepartment of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Anna C E HurstDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Alesha HicksDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Mohnish SuriNottingham Clinical Genetics Service, City Hospital Campus, Nottingham, UK.
Ermal AliuDepartment of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Sunil NaikDepartment of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Richard SidlowValley Children's Hospital, Valley Children's Place, Madera, CA 93636, USA.
Juliette CoursimaultUniversity Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France.
Gaël NicolasUniversity Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France.
Hanna KüpperNeuropediatric Department, University Hospital Tübingen, Tübingen, Germany.
Florence PetitCentre Hospitalier Universitaire de Lille, Clinique de Génétique Guy Fontaine, Lille, France.
Veyan IbrahimDalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada; Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
Deniz TopDalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada; Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
Francesca Di CaraDepartment of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
Genomics England Research ConsortiumGenomics England, London, UK.
Raymond J LouieGreenwood Genetic Center, Greenwood, SC, USA.
Elliot StolermanGreenwood Genetic Center, Greenwood, SC, USA.
Han G BrunnerRadboudumc, Department of Human Genetics, Nijmegen, the Netherlands; Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands.
Lisenka E L M VissersRadboudumc, Department of Human Genetics, Nijmegen, the Netherlands.
Jamie M KramerDalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada. Electronic address: jkramer@dal.ca.
Tjitske KleefstraRadboudumc, Department of Human Genetics, Nijmegen, the Netherlands; Center for Neuropsychiatry, Vincent van Gogh, Venray, the Netherlands; Department of Clinical Genetics, ErasmusMC, Rotterdam, the Netherlands. Electronic address: t.kleefstra@erasmusmc.nl.
Inserm · FRRadboud University Nijmegen · NLDalhousie University · CAGreenwood Genetic Center · USUniversity of Tübingen · DEAzienda Sanitaria Unità Locale di Reggio Emilia · ITChild Health and Development Institute · USGoethe University Frankfurt · DEUniversität Hamburg · DEUniversity Medical Center Utrecht · NLUniversity of South Dakota · USBaylor College of Medicine · USCambridge University Hospitals NHS Foundation Trust · GBCentre National de la Recherche Scientifique · FRCornell University · USHospitais da Universidade de Coimbra · PTIstituto Giannina Gaslini · ITMaastricht University · NLNebraska Medical Center · USNew South Wales Department of Health · AU
Funding
CIHR PJT 469689
Abstract
De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
Indexed as
Intellectual DisabilityNeurodevelopmental DisordersAnimalsDrosophilaFaciesHumansJumonji Domain-Containing Histone DemethylasesPhenotypeJumonji Domain-Containing Histone DemethylasesKDM6B protein, humanCOMPASSde novo variantsDrosophilaKDM6BMendelian disordersmissense variantsneurodevelopmental disorders
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