2. Academic Validation
  3. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

  • Am J Hum Genet. 2020 Dec 3;107(6):1170-1177. doi: 10.1016/j.ajhg.2020.11.001.
Anna R Duncan 1,  Antonio Vitobello 2,  Stephan C Collins 3,  Valerie E Vancollie 4,  Christopher J Lelliott 4,  Lance Rodan 5,  Jiahai Shi 6,  Ann R Seman 7,  Emanuele Agolini 8,  Antonio Novelli 8,  Paolo Prontera 9,  Maria J Guillen Sacoto 10,  Teresa Santiago-Sim 10,  Aurélien Trimouille 11,  Cyril Goizet 12,  Mathilde Nizon 13,  Ange-Line Bruel 14,  Christophe Philippe 14,  Patricia E Grant 15,  Monica H Wojcik 16,  Joan Stoler 7,  Casie A Genetti 17,  Marieke F van Dooren 18,  Saskia M Maas 19,  Marielle Alders 19,  Laurence Faivre 2,  Arthur Sorlin 20,  Grace Yoon 21,  Binnaz Yalcin 22,  Pankaj B Agrawal 23
Affiliations

Affiliations

  • 1 Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 2 Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France; INSERM UMR1231 GAD, Université de Bourgogne Franche-Comté, 21000 Dijon, France; Centre de Référence Maladies Rares « Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.
  • 3 INSERM UMR1231 GAD, Université de Bourgogne Franche-Comté, 21000 Dijon, France.
  • 4 Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • 5 Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 6 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR.
  • 7 Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 8 Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital, 00146 Rome, Italy.
  • 9 Medical Genetics Unit, Maternal-Infantile Department, Hospital and University of Perugia, 06129 Perugia, Italy.
  • 10 Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA.
  • 11 Department of Medical Genetics, University Hospital of Bordeaux, 33076 Bordeaux, France.
  • 12 Reference Center for Neurogenetics, Department of Medical Genetics, University Hospital of Bordeaux, 33076 Bordeaux, France.
  • 13 CHU Nantes, Genetic Medical Department, 44093 Nantes, France.
  • 14 Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France; INSERM UMR1231 GAD, Université de Bourgogne Franche-Comté, 21000 Dijon, France.
  • 15 Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 16 Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 17 Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
  • 18 Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
  • 19 Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
  • 20 Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France; INSERM UMR1231 GAD, Université de Bourgogne Franche-Comté, 21000 Dijon, France; Centre de Référence Maladies Rares « Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France; Centre de Référence Maladies Rares « Déficiences Intellectuelles de Causes Rares », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.
  • 21 Divisions of Neurology and Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 22 INSERM UMR1231 GAD, Université de Bourgogne Franche-Comté, 21000 Dijon, France. Electronic address: binnaz.yalcin@inserm.fr.
  • 23 Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: pagrawal@enders.tch.harvard.edu.
PMID: 33232677 DOI: 10.1016/j.ajhg.2020.11.001
Abstract

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and Cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

Keywords

JMJD2B; KDM4B; agenesis of the corpus callosum; dysmorphic hippocampi; global developmental delay; heterozygous variant; intellectual disability; neurodevelopmental disorder.

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