Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.
The American Journal of Human Genetics. 2020-12-01; 107(6): 1170-1177
DOI: 10.1016/j.ajhg.2020.11.001
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1. Am J Hum Genet. 2020 Dec 3;107(6):1170-1177. doi: 10.1016/j.ajhg.2020.11.001.
Epub 2020 Nov 23.
Heterozygous Variants in KDM4B Lead to Global Developmental Delay and
Neuroanatomical Defects.
Duncan AR(1), Vitobello A(2), Collins SC(3), Vancollie VE(4), Lelliott CJ(4),
Rodan L(5), Shi J(6), Seman AR(7), Agolini E(8), Novelli A(8), Prontera P(9),
Guillen Sacoto MJ(10), Santiago-Sim T(10), Trimouille A(11), Goizet C(12), Nizon
M(13), Bruel AL(14), Philippe C(14), Grant PE(15), Wojcik MH(16), Stoler J(7),
Genetti CA(17), van Dooren MF(18), Maas SM(19), Alders M(19), Faivre L(2), Sorlin
A(20), Yoon G(21), Yalcin B(22), Agrawal PB(23).
Author information:
(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: .
(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:
.
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.
Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc.
All rights reserved.
DOI: 10.1016/j.ajhg.2020.11.001
PMCID: PMC7820620
PMID: 33232677 [Indexed for MEDLINE]