2. Academic Validation
  3. ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder

ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder

  • Am J Hum Genet. 2019 Feb 7;104(2):319-330. doi: 10.1016/j.ajhg.2018.12.007.
Raphael Carapito 1,  Ekaterina L Ivanova 2,  Aurore Morlon 3,  Linyan Meng 4,  Anne Molitor 5,  Eva Erdmann 2,  Bruno Kieffer 2,  Angélique Pichot 5,  Lydie Naegely 5,  Aline Kolmer 5,  Nicodème Paul 5,  Antoine Hanauer 5,  Frédéric Tran Mau-Them 6,  Nolwenn Jean-Marçais 6,  Susan M Hiatt 7,  Gregory M Cooper 7,  Tatiana Tvrdik 8,  Alison M Muir 9,  Clémantine Dimartino 10,  Maya Chopra 11,  Jeanne Amiel 12,  Christopher T Gordon 10,  Fabien Dutreux 5,  Aurore Garde 6,  Christel Thauvin-Robinet 6,  Xia Wang 4,  Magalie S Leduc 4,  Meredith Phillips 13,  Heather P Crawford 13,  Mary K Kukolich 13,  David Hunt 14,  Victoria Harrison 14,  Mira Kharbanda 14,  Deciphering Developmental Disorders Study 15,  University of Washington Center for Mendelian Genomics,  Robert Smigiel 16,  Nina Gold 17,  Christina Y Hung 17,  David H Viskochil 18,  Sarah L Dugan 18,  Pinar Bayrak-Toydemir 19,  Géraldine Joly-Helas 20,  Anne-Marie Guerrot 20,  Caroline Schluth-Bolard 21,  Marlène Rio 22,  Ingrid M Wentzensen 23,  Kirsty McWalter 23,  Rhonda E Schnur 23,  Andrea M Lewis 24,  Seema R Lalani 24,  Noël Mensah-Bonsu 25,  Jocelyn Céraline 26,  Zijie Sun 27,  Rafal Ploski 28,  Carlos A Bacino 24,  Heather C Mefford 9,  Laurence Faivre 6,  Olaf Bodamer 29,  Jamel Chelly 30,  Bertrand Isidor 31,  Seiamak Bahram 32
Affiliations

Affiliations

  • 1 Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085 Strasbourg, France; Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091 Strasbourg, France. Electronic address: [email protected].
  • 2 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U1258, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
  • 3 BIOMICA SAS, 4 rue Boussingault, 67000 Strasbourg, France.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
  • 5 Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085 Strasbourg, France.
  • 6 Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), CHU de Dijon Bourgogne, 21079 Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France.
  • 7 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • 8 ARUP Laboratories, Salt Lake City, UT 84108, USA.
  • 9 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 10 Laboratory of Embryology and Genetics of Human Malformations, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité Université, Imagine Institute, 75015 Paris, France.
  • 11 Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; Discipline of Genetic Medicine, University of Sydney, Sydney, NSW 2050, Australia.
  • 12 Laboratory of Embryology and Genetics of Human Malformations, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité Université, Imagine Institute, 75015 Paris, France; Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.
  • 13 Cook Children's Medical Center, Fort Worth, TX 76102, USA.
  • 14 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
  • 15 The Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • 16 Department of Pediatrics and Rare Disorders, Wroclaw Medical University, 50-368 Wroclaw, Poland.
  • 17 Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 18 Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
  • 19 ARUP Laboratories, Salt Lake City, UT 84108, USA; Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
  • 20 Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, 76821 Rouen, France.
  • 21 Department of Genetics, Hospices Civils de Lyon, GENDEV Team, Neurosciences Research Center of Lyon, INSERM U1028, CNRS UMR5292, UCBL1, 69677 Bron, France.
  • 22 Paris Descartes-Sorbonne Paris Cité Université, Imagine Institute, 75015 Paris, France; Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.
  • 23 GeneDx Inc., Gaithersburg, MD 20877, USA.
  • 24 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 25 Texas Children's Hospital, Houston, TX 77030, USA.
  • 26 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U1258, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France; Service d'Onco-Hématologie, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.
  • 27 Comprehensive Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
  • 28 Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
  • 29 Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
  • 30 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U1258, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France; Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France.
  • 31 Service de Génétique Médicale, Hôpital Hôtel-Dieu, CHU de Nantes, 44093 Nantes, France.
  • 32 Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085 Strasbourg, France; Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091 Strasbourg, France. Electronic address: [email protected].
PMID: 30639322 DOI: 10.1016/j.ajhg.2018.12.007
Abstract

ZMIZ1 is a coactivator of several transcription factors, including p53, the Androgen Receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the Androgen Receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

Keywords

ZMIZ1; intellectual disability; neurodevelopmental disorder; neuronal positioning; transcriptional coactivation.

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