title: 20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition.
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.
authors.affiliation: 1] IGBMC, CNRS UMR 7104/INSERM U964/University of Strasbourg, Illkirch Cedex, France [2] Chaire de Génétique Humaine, Collège de France, Paris, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Piton
authors.affiliation: 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.
authors.forename: Hélène
authors.initials: H
authors.lastname: Poquet
authors.affiliation: 1] IGBMC, CNRS UMR 7104/INSERM U964/University of Strasbourg, Illkirch Cedex, France [2] Chaire de Génétique Humaine, Collège de France, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Redin
authors.affiliation: Centre de génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, Dijon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel
authors.affiliation: Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Lauer
authors.affiliation: 1] IGBMC, CNRS UMR 7104/INSERM U964/University of Strasbourg, Illkirch Cedex, France [2] Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Muller
authors.affiliation: 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.
authors.forename: Julien
authors.identifier: 0000000192713961
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Herenger
authors.affiliation: 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chancenotte
authors.affiliation: Centre Référent des Troubles du Langage et des Apprentissages, Hôpital d'Enfants, Dijon, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Bonnet
authors.affiliation: Service de Pédopsychiatrie, Hôpital d'Enfants, Dijon, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pinoit
authors.affiliation: Centre de génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, Dijon, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Huet
authors.affiliation: 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.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.affiliation: Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jaeger
authors.affiliation: IGBMC, Microarray and Sequencing Platform, Illkirch, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Gras
authors.affiliation: IGBMC, Microarray and Sequencing Platform, Illkirch, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jost
authors.affiliation: Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gérard
authors.affiliation: Service de Biochimie et de Biologie Moléculaire, Groupe Hospitalier Universitaire Saint-Louis Lariboisière Fernand-Widal, AP-HP, Paris, France.
authors.forename: Katell
authors.initials: K
authors.lastname: Peoc'h
authors.affiliation: Service de Biochimie et de Biologie Moléculaire, Groupe Hospitalier Universitaire Saint-Louis Lariboisière Fernand-Widal, AP-HP, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: 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.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
mesh_terms: D000595:Amino Acid Sequence; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000235:genetics*; D001483:Base Sequence; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary
chemical_list: D008995:Monoamine Oxidase