ArticleAmerican journal of human genetics2022
Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.
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Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 33 citations in OpenAlex.
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Authors and funding
66 authors at 20 institutions in 12 countries.
Federico TessadoriHubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 Utrecht, the Netherlands.
Karen DuranDepartment of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands.
Karen KnappDepartment of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Matthias FellnerDepartment of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Deciphering Developmental Disorders Study
Sarah SmithsonBristol Regional Genetics Service, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS2 8EG, UK.
Ana Beleza MeirelesBristol Regional Genetics Service, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS2 8EG, UK.
Mariet W EltingAmsterdam UMC, Afdeling Klinische genetica, 1081 Amsterdam, the Netherlands.
Quinten WaisfiszAmsterdam UMC, Afdeling Klinische genetica, 1081 Amsterdam, the Netherlands.
Anne O'Donnell-LuriaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
Catherine NowakManton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
Jessica DouglasManton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
Anne RonanClinical Genetics, Hunter Genetics Unit, Waratah, NSW 2298, Australia.
Theresa BrunetInstitute of Medical Genetics, 81675 Munchen, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Urania KotzaeridouDivision of Child Neurology and Inherited Metabolic Diseases, Department of Pediatrics, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Shayna SvihovecSection of Genetics and Metabolism, Department of Pediatrics, The Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Margarita S SaenzSection of Genetics and Metabolism, Department of Pediatrics, The Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Isabelle ThiffaultUniversity of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA; Center for Genomic Medicine, Children's Mercy Research Institute, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
Florencia Del VisoCenter for Genomic Medicine, Children's Mercy Research Institute, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
Patrick DevineInstitute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
Shannon RegoInstitute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
Jessica TenneyDivision of Medical Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
Arie van HaeringenDepartment of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Claudia A L RuivenkampDepartment of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Saskia KoeneDepartment of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Stephen P RobertsonDepartment of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Charulata DeshpandeGuy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
Rolph PfundtDepartment of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
Nienke VerbeekDepartment of Genetics, University Medical Centre Utrecht, 3584 CX Utrecht, the Netherlands.
Jiddeke M van de KampDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
Janneke M M WeissDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
Anna RuizGenetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, 08208 Sabadell, Spain.
Elisabeth GabauPaediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, 08208 Sabadell, Barcelona, Spain.
Ehud BanneKaplan Medical Center, Clalit Health Services, Rehovot 76100, Israel.
Alexander PeplerPraxis für Humangenetik Tübingen, 72076 Tuebingen, Germany.
Armand BottaniService of Genetic Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
Sacha LaurentDepartment of Genetic Medicine, University Hospitals of Geneva and University of Geneva Medical Faculty, Geneva 1211, Switzerland.
Michel GuipponiDepartment of Genetic Medicine, University Hospitals of Geneva and University of Geneva Medical Faculty, Geneva 1211, Switzerland.
Emilia BijlsmaDepartment of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Ange-Line BruelUMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, 21078 Dijon, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Dijon Bourgogne University Hospital, 21079 Dijon, France.
Arthur SorlinCentre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs," Centre de Génétique, FHU-TRANSLAD, Dijon Bourgogne University Hospital, 21079 Dijon, France.
Mary WillisDepartment of Pediatrics, Naval Medical Center San Diego, San Diego, CA 92134, USA.
Zoe PowisAmbry Genetics, CA 92656, USA.
Thomas SmolUniv. Lille, RADEME EA7364, CHU Lille, Institut de Génétique Médicale, 59000 Lille, France.
Catherine Vincent-DelormeDepartment of Clinical Genetics, CHU Lille, 59000 Lille, France.
Diana BaralleFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
Estelle ColinService de Génétique Médicale, CHU d'Angers, 49933 Angers, France.
Nicole RevencuCenter for Human Genetics, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.
Eduardo CalpenaMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Andrew O M WilkieMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Maya ChopraRosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA.
Valerie Cormier-DaireUniversité de Paris, Department of Clinical Genetics and Reference Centre for Constitutional Bone Diseases, INSERM U1163, Imagine Institute, Necker-Enfants Malades Hospital, AP-HP, 75015 Paris, France.
Boris KerenGenetic Department, APHP, Sorbonne Université, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.
Alexandra AfenjarCRMR Malformations et Maladies Congénitales du Cervelet et Déficiences Intellectuelles de Causes Rares, Département de Génétique, Sorbonne Université, AP-HP, Hôpital Trousseau, 75012 Paris, France.
Marcello NicetaArea di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Alessandra TerraccianoArea di Ricerca Medicina Multimodale di Laboratorio, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Nicola SpecchioArea di Ricerca Scienze Neurologiche e Medicina Riabilitativa, Ospedale Pediatrico Bambino Gesù, IRCCS, 00163 Rome, Italy.
Marco TartagliaArea di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Marlene RioDepartment of Genetics, Necker Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France.
Giulia BarciaDepartment of Genetics, Necker Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France.
Sophie RondeauDepartment of Genetics, Necker Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France.
Cindy ColsonCHU Lille, Clinique de Génétique, 59000 Lille, France.
Jeroen BakkersHubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 Utrecht, the Netherlands; Department of Pediatric Cardiology, Division of Pediatrics, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
Peter D MaceDepartment of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Louise S BicknellDepartment of Biochemistry, University of Otago, Dunedin 9016, New Zealand. Electronic address: louise.bicknell@otago.ac.nz.
Gijs van HaaftenDepartment of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, the Netherlands. Electronic address: g.vanhaaften@umcutrecht.nl.
Boston Children's Hospital · USUniversity of Otago · NZBambino Gesù Children's Hospital · ITLeiden University Medical Center · NLDélégation Paris 5 · FRUniversity of California, San Francisco · USUtrecht University · NLAmsterdam University Medical Centers · NLCentre Hospitalier Universitaire de Lille · FRChildren's Hospital Colorado · USChildren's Mercy Hospital · USInserm · FRJohn Radcliffe Hospital · GBSorbonne Université · FRUniversitat Autònoma de Barcelona · ESUniversity Hospitals Bristol NHS Foundation Trust · GBUniversity Medical Center Utrecht · NLUniversity of Geneva · CHAmbry Genetics (United States) · USBroad Institute · US
Funding
Wellcome TrustWellcome Trust WT098051
Abstract
Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.
Indexed as
HistonesZebrafishAnimalsChromatinDNAHumansSyndromeChromatinDNAHistoneshistone H4intellectual disabilitymicrocephalyneurodevelopmental disordernucleosomezebrafish
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