2. Academic Validation
  3. 20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

  • Eur J Hum Genet. 2014 Jun;22(6):776-83. doi: 10.1038/ejhg.2013.243.
Amélie Piton 1,  Hélène Poquet 2,  Claire Redin 1,  Alice Masurel 3,  Julia Lauer 4,  Jean Muller 5,  Julien Thevenon 6,  Yvan Herenger 4,  Sophie Chancenotte 7,  Marlène Bonnet 8,  Jean-Michel Pinoit 9,  Frédéric Huet 3,  Christel Thauvin-Robinet 6,  Anne-Sophie Jaeger 4,  Stéphanie Le Gras 10,  Bernard Jost 10,  Bénédicte Gérard 4,  Katell Peoc'h 11,  Jean-Marie Launay 11,  Laurence Faivre 6,  Jean-Louis Mandel 12
Affiliations

Affiliations

  • 1 1] IGBMC, CNRS UMR 7104/INSERM U964/University of Strasbourg, Illkirch Cedex, France [2] Chaire de Génétique Humaine, Collège de France, Paris, France.
  • 2 1] Centre de génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, Dijon, France [2] Service de Pédopsychiatrie, Hôpital d'Enfants, Dijon, France.
  • 3 Centre de génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, Dijon, France.
  • 4 Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
  • 5 1] IGBMC, CNRS UMR 7104/INSERM U964/University of Strasbourg, Illkirch Cedex, France [2] Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
  • 6 1] Centre de génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, Dijon, France [2] EA 4271 GAD, Faculté de Médecine, Université de Bourgogne, Dijon, France.
  • 7 1] Centre de génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, Dijon, France [2] Centre Référent des Troubles du Langage et des Apprentissages, Hôpital d'Enfants, Dijon, France.
  • 8 Centre Référent des Troubles du Langage et des Apprentissages, Hôpital d'Enfants, Dijon, France.
  • 9 Service de Pédopsychiatrie, Hôpital d'Enfants, Dijon, France.
  • 10 IGBMC, Microarray and Sequencing Platform, Illkirch, France.
  • 11 Service de Biochimie et de Biologie Moléculaire, Groupe Hospitalier Universitaire Saint-Louis Lariboisière Fernand-Widal, AP-HP, Paris, France.
  • 12 1] IGBMC, CNRS UMR 7104/INSERM U964/University of Strasbourg, Illkirch Cedex, France [2] Chaire de Génétique Humaine, Collège de France, Paris, France [3] Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
PMID: 24169519 DOI: 10.1038/ejhg.2013.243
Abstract

Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with >250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X-linked gene encoding Monoamine Oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene-environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients.

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