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1. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

Author

Claire S Leblond, Jutta Heinrich, Richard Delorme, Christian Proepper, Catalina Betancur, Guillaume Huguet, Marina Konyukh, Pauline Chaste, Elodie Ey, Maria Rastam, Henrik Anckarsäter, Gudrun Nygren, I Carina Gillberg, Jonas Melke, Roberto Toro, Beatrice Regnault, Fabien Fauchereau, Oriane Mercati, Nathalie Lemière, David Skuse, Martin Poot, Richard Holt, Anthony P Monaco, Irma Järvelä, Katri Kantojärvi, Raija Vanhala, Sarah Curran, David A Collier, Patrick Bolton, Andreas Chiocchetti, Sabine M Klauck, Fritz Poustka, Christine M Freitag, Regina Waltes, Marnie Kopp, Eftichia Duketis, Elena Bacchelli, Fiorella Minopoli, Liliana Ruta, Agatino Battaglia, Luigi Mazzone, Elena Maestrini, Ana F Sequeira, Barbara Oliveira, Astrid Vicente, Guiomar Oliveira, Dalila Pinto, Stephen W Scherer, Diana Zelenika, Marc Delepine, Mark Lathrop, Dominique Bonneau, Vincent Guinchat, Françoise Devillard, Brigitte Assouline, Marie-Christine Mouren, Marion Leboyer, Christopher Gillberg, Tobias M Boeckers, and Thomas Bourgeron

Subjects
Genetics, QH426-470
Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Published
2012
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2. Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations.

Author

Marina Konyukh, Richard Delorme, Pauline Chaste, Claire Leblond, Nathalie Lemière, Gudrun Nygren, Henrik Anckarsäter, Maria Rastam, Ola Ståhlberg, Frederique Amsellem, I Carina Gillberg, Marie Christine Mouren-Simeoni, Evelyn Herbrecht, Fabien Fauchereau, Roberto Toro, Christopher Gillberg, Marion Leboyer, and Thomas Bourgeron

Subjects
Medicine, Science
Abstract

BackgroundAutism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate.Methodology/principal findingsWe further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls.Conclusions/significanceOur results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD.

Published
2011
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3. Copy number variants calling from WES data through eXome hidden Markov model (XHMM) identifies additional 2.5% pathogenic genomic imbalances smaller than 30 kb undetected by array-CGH

Author

Emilie Tisserant, Antonio Vitobello, Davide Callegarin, Simon Verdez, Ange‐line Bruel, Ludwig Serge Aho Glele, Arthur Sorlin, Eleonore Viora‐Dupont, Marina Konyukh, Nathalie Marle, Sophie Nambot, Sébastien Moutton, Caroline Racine, Aurore Garde, Julian Delanne, Frédéric Tran‐Mau‐Them, Christophe Philippe, Paul Kuentz, Marlène Poulleau, Muriel Payet, Charlotte Poe, Christel Thauvin‐Robinet, Laurence Faivre, Anne‐Laure Mosca‐Boidron, Julien Thevenon, Yannis Duffourd, and Patrick Callier

Subjects
Comparative Genomic Hybridization, DNA Copy Number Variations, Intellectual Disability, Exome Sequencing, Genetics, Humans, Exome, Genomics, Genetics (clinical)
Abstract

It has been estimated that Copy Number Variants (CNVs) account for 10%-20% of patients affected by Developmental Disorder (DD)/Intellectual Disability (ID). Although array comparative genomic hybridization (array-CGH) represents the gold-standard for the detection of genomic imbalances, common Agilent array-CGH 4 × 180 kb arrays fail to detect CNVs smaller than 30 kb. Whole Exome sequencing (WES) is becoming the reference application for the detection of gene variants and makes it possible also to infer genomic imbalances at single exon resolution. However, the contribution of small CNVs in DD/ID is still underinvestigated. We made use of the eXome Hidden Markov Model (XHMM) software, a tool utilized by the ExAC consortium, to detect CNVs from whole exome sequencing data, in a cohort of 200 unsolved DD/DI patients after array-CGH and WES-based single nucleotide/indel variant analyses. In five out of 200 patients (2.5%), we identified pathogenic CNV(s) smaller than 30 kb, ranging from one to six exons. They included two heterozygous deletions in TCF4 and STXBP1 and three homozygous deletions in PPT1, CLCN2, and PIGN. After reverse phenotyping, all variants were reported as causative. This study shows the interest in applying sequencing-based CNV detection, from available WES data, to reduce the diagnostic odyssey of additional patients unsolved DD/DI patients and compare the CNV-detection yield of Agilent array-CGH 4 × 180kb versus whole exome sequencing.

Published
2021

4. CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders

Author

Thomas Rolland, Marion Leboyer, Isabelle Cloëz-Tayarani, Stephen W. Scherer, Laurence Faivre, Matthew J. Gazzellone, Marc Delepine, Marina Konyukh, Anne-Laure Mosca-Boidron, Anna Maruani, Martine François, Guillaume Huguet, Ryan K. C. Yuen, Béatrice Regnault, Thomas Bourgeron, Dominique Bonneau, Maria Råstam, Kazutada Watanabe, Marion Benabou, Anne Danckaert, J Van-Gils, Richard Delorme, Yasushi Shimoda, Susan Walker, Gwenaëlle André-Leroux, Marco Bellinzoni, Anita Beggiato, Laura Gouder, Anne Boland, T Van Den Abbeele, Christopher Gillberg, Frédérique Amsellem, Alexandre Mathieu, J-P Bourgeois, Oriane Mercati, Julien Buratti, Cloëz-Tayarani, Isabelle, Maladies Neurologiques et Psychiatriques - Genes synaptiques de l'autisme et du retard mental - - SynGen-ASD-LD2008 - ANR-08-MNPS-0037 - MNP - VALID, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imagopole (CITECH), Institut Pasteur [Paris] (IP), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children [Toronto] (SickKids), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génotypage des Eucaryotes (Plate-Forme), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Nagaoka University of Technology, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Lund University [Lund], University of Gothenburg (GU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fondation FondaMental [Créteil], McLaughlin Centre, University of Toronto, This work was funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, Centre National de la Recherche Scientifique, University Paris Diderot, Agence Nationale de la Recherche (ANR-08-MNPS-037-01- SynGen), the Conny-MaevaCharitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the Fondamental Foundation, the GenMed Labex and the BioPsy labex. O Mercati was supported by an undergraduate fellowship from the Neuropole de Recherche Francilien (NeRF) and the Orange Foundation. The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed offinancial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’in kind contribution. Control data sets were obtained,along with permission for use, from the database of Genotypes and Phenotypes (dbGaP) found at http://www-ncbi-nlm-nih-gov.myaccess.library.utoronto.ca/gap through accession numbers phs000169.v1.p1 (Whole Genome Association Study of Visceral Adiposity in the HABC Study), phs000303.v1.p1 (Genetic Epidemiology of Refractive Error in the KORA Study) and phs000404.v1.p1 (COGEND, the Genetic Architecture of Smoking and Smoking Cessation). Support for the‘CIDR VisceralAdiposity Study’ was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Health ABC Study (HABC) Investigators. The KORA data set was obtained from the NEI Refractive Error Collaboration (NEIREC) Database, support for which was provided by the National Eye Institute. Support for genotyping of the COGEND samples, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. Assistance with genotype cleaning of the COGEND samples, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) CoordinatingCenter (U01HG004446). Support for the collection of COGEND data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND, P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). The contents of this article are solely the responsibility of the authors and do not necessarily represent the officialviews of the NIH., ANR-08-MNPS-0037,SynGen-ASD-LD,Genes synaptiques de l'autisme et du retard mental(2008), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Centre National de la Recherche Scientifique ( CNRS ) -Institut Pasteur [Paris], Gènes, Synapses et Cognition, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] ( MaIAGE ), Institut National de la Recherche Agronomique ( INRA ), Microbiologie structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), The Hospital for sick children [Toronto] ( SickKids ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Université d'Angers ( UA ) -CHU Angers, University of Gothenburg ( GU ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Fondation FondaMental, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, and ANR-08-MNPS-0037,SynGen-ASD-LD,Genes synaptiques de l'autisme et du retard mental ( 2008 )

Subjects
Male, 0301 basic medicine, genetic structures, Autism Spectrum Disorder, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, medicine.disease_cause, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics, Mutation, Psychiatry and Mental health, Schizophrenia, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Auditory Perception, Medical genetics, Original Article, Female, Psychopharmacology, medicine.symptom, Psychology, Adult, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, behavioral disciplines and activities, 03 medical and health sciences, Cellular and Molecular Neuroscience, Contactins, mental disorders, medicine, Humans, Dementia, Genetic Predisposition to Disease, Molecular Biology, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Hyperacusis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Attention Deficit Disorder with Hyperactivity, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Behavioral medicine, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Autism, Neuroscience
Abstract

International audience; Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6(W923X) was transmitted by a mother to her two sons with ASD and one variant CNTN6(P770L) was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

Published
2016

5. Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders

Author

Guillaume Huguet, Gudrun Nygren, Ralf Jockers, Maria Råstam, Jonas Melke, Marina Konyukh, Roberto Toro, Jean-Marie Launay, Hany Goubran Botros, I. Carina Gillberg, Henrik Anckarsäter, Christopher Gillberg, Jean-Luc Guillaume, Fabien Fauchereau, Nathalie Clement, Thomas Bourgeron, Richard Delorme, Isabelle Scheid, Marion Leboyer, Pauline Chaste, Claire S. Leblond, Nathalie Lemière, Lydia Boudarene, Cécile Pagan, Emilie Serrano, Ola Ståhlberg, and Christelle M. Durand

Subjects
medicine.medical_specialty, Mutation, education.field_of_study, Splice site mutation, Population, Biology, medicine.disease_cause, Melatonin, Endocrinology, Acetylserotonin O-methyltransferase, GPR50, Internal medicine, Genetic variation, medicine, Genetic variability, education, medicine.drug
Abstract

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.

Published
2011

6. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders

Author

Christian Proepper, Dominique Bonneau, Catalina Betancur, Sarah Curran, Astrid M. Vicente, Henrik Anckarsäter, Elena Bacchelli, Sabine M. Klauck, Eftichia Duketis, Guiomar Oliveira, Fabien Fauchereau, Richard Delorme, Irma Järvelä, I. Carina Gillberg, Marina Konyukh, Stephen W. Scherer, Pauline Chaste, Elena Maestrini, Guillaume Huguet, Dalila Pinto, David Skuse, Marie-Christine Mouren, Béatrice Regnault, Nathalie Lemière, Jonas Melke, Christopher Gillberg, Bárbara Oliveira, Maria Råstam, Thomas Bourgeron, Marnie Kopp, Marc Delepine, Oriane Mercati, Raija Vanhala, Luigi Mazzone, Marion Leboyer, Richard Holt, Agatino Battaglia, Fiorella Minopoli, Katri Kantojärvi, Diana Zelenika, Liliana Ruta, Roberto Toro, Ana Filipa Sequeira, Françoise Devillard, Brigitte Assouline, Martin Poot, Elodie Ey, Regina Waltes, Vincent Guinchat, Tobias M. Boeckers, Jutta Heinrich, Anthony P. Monaco, Gudrun Nygren, Fritz Poustka, Mark Lathrop, David A. Collier, Claire S. Leblond, Patrick Bolton, Christine M. Freitag, Andreas G. Chiocchetti, Betancur, Catalina, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Ulm - Ulm University [Ulm, Allemagne], Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Forensic Psychiatry, Lund University [Lund], Department of Pharmacology, Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Behavioural and Brain Sciences Unit, Institute of Child Health, University College of London [London] (UCL), University Medical Center [Utrecht], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King‘s College London, Social, Genetic and Developmental Psychiatry Centre (SGDP), Institute of psychiatry, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Biotechnology, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Division of Child Neurology and Psychiatry, Department of Paediatrics, Università degli studi di Catania = University of Catania (Unict), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire Intégrée (BNVI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute for Anatomy and Cell Biology, Department of Medical and Clinical Genetics, Leblond C.S., Heinrich J., Delorme R., Proepper C., Betancur C., Huguet G., Konyukh M., Chaste P| Ey E., Rastam M., Anckarsäter H., Nygren G., Gillberg IC., Melke J., Toro R., Regnault B., Fauchereau F., Mercati O., Lemière N., Skuse D., Poot M., Holt R., Monaco A.P., Järvelä I., Kantojärvi K., Vanhala R., Curran S., Collier D.A., Bolton P., Chiocchetti A., Klauck S.M., Poustka F., Freitag C.M., Waltes R., Kopp M., Duketis E., Bacchelli E., Minopoli F., Ruta L., Battaglia A., Mazzone L., Maestrini E., Sequeira A.F., Oliveira B., Vicente A., Oliveira G., Pinto D., Scherer S.W., Zelenika D., Delepine M., Lathrop M., Bonneau D., Guinchat V., Devillard F., Assouline B., Mouren M.C., Leboyer M., Gillberg C., Boeckers T.M., Bourgeron T., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Anatomy and Cell Biology, Ulm University, University of Lund, Institut Pasteur [Paris], University of Oxford [Oxford], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Università degli studi di Catania [Catania], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
Male, Gene Dosage, Receptors, Nicotinic, MESH: Protein Isoforms, HIDDEN-MARKOV MODEL, 0302 clinical medicine, MESH: Child, Protein Isoforms, Tissue Distribution, MESH: Nerve Tissue Proteins, Child, Neurons, 0303 health sciences, MESH: Alternative Splicing, PSYCHIATRIC-DISORDERS, CHRNA7, MESH: Sequence Deletion, 3. Good health, Autism spectrum disorder, Child, Preschool, Medicine, Adaptor Proteins, Signal Transducing, Adult, Alternative Splicing, Cell Line, Child Development Disorders, Pervasive, Female, Gene Expression Regulation, Humans, Nerve Tissue Proteins, RNA Splice Sites, Sequence Deletion, Synapses, alpha7 Nicotinic Acetylcholine Receptor, Child Development Disorders, education, COPY-NUMBER VARIATION, Molecular Genetics, 03 medical and health sciences, Genetics, AUTISM, MESH: Tissue Distribution, Molecular Biology, Biology, SNP GENOTYPING DATA, Ecology, Evolution, Behavior and Systematics, Pervasive, MESH: Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, RECURRENT MICRODELETIONS, MESH: Child, Preschool, Signal Transducing, MESH: Adult, SCAFFOLDING PROTEIN SHANK3, medicine.disease, Human genetics, MESH: Cell Line, MESH: Female, 030217 neurology & neurosurgery, Neuroscience, Cancer Research, MESH: Neurons, MESH: RNA Splice Sites, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, Nicotinic, MESH: Child Development Disorders, Pervasive, MESH: Gene Dosage, MESH: Synapses, POSTSYNAPTIC DENSITY, Receptors, Copy-number variation, Genetics (clinical), Psychiatry, Adaptor Proteins, MESH: Gene Expression Regulation, Settore MED/39 - Neuropsichiatria Infantile, SHANK2, Mental Health, MESH: Receptors, Nicotinic, Research Article, lcsh:QH426-470, 15Q13.3 MICRODELETIONS, Genetic variation, mental disorders, medicine, ddc:610, Preschool, Gene, 030304 developmental biology, MESH: Male, lcsh:Genetics, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, biology.protein, Autism, 3111 Biomedicine, MENTAL-RETARDATION
Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While mutations in several genes have been identified in patients with ASD, little is known about their effects on neuronal function and their interaction with other genetic variations. Using a combination of genetic and functional approaches, we identified novel SHANK2 mutations including a de novo loss of one copy of the SHANK2 gene in a patient with autism and several mutations observed in patients that reduced neuronal cell contacts in vitro. Further genomic analysis of three patients carrying de novo SHANK2 deletions identified additional rare genomic imbalances previously associated with neuropsychiatric disorders. Taken together, these results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Published
2012

7. Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders

Author

Pauline, Chaste, Nathalie, Clement, Hany Goubran, Botros, Jean-Luc, Guillaume, Marina, Konyukh, Cécile, Pagan, Isabelle, Scheid, Gudrun, Nygren, Henrik, Anckarsäter, Maria, Rastam, Ola, Ståhlberg, I Carina, Gillberg, Jonas, Melke, Richard, Delorme, Claire, Leblond, Roberto, Toro, Guillaume, Huguet, Fabien, Fauchereau, Christelle, Durand, Lydia, Boudarene, Emilie, Serrano, Nathalie, Lemière, Jean Marie, Launay, Marion, Leboyer, Ralf, Jockers, Christopher, Gillberg, and Thomas, Bourgeron

Subjects
Acetylserotonin O-Methyltransferase, Male, Attention Deficit Disorder with Hyperactivity, Receptor, Melatonin, MT1, Genetic Variation, Humans, Female, Nerve Tissue Proteins, Arylalkylamine N-Acetyltransferase, Melatonin, Receptors, G-Protein-Coupled
Abstract

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2TC) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.

Published
2011

8. Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations

Author

Maria Råstam, I. Carina Gillberg, Thomas Bourgeron, Roberto Toro, Marie Christine Mouren-Simeoni, Ola Ståhlberg, Marina Konyukh, Frédérique Amsellem, Richard Delorme, Henrik Anckarsäter, Christopher Gillberg, Nathalie Lemière, Marion Leboyer, Fabien Fauchereau, Pauline Chaste, Claire S. Leblond, Gudrun Nygren, Evelyn Herbrecht, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Göteborgs Universitet (GU), Lund University [Lund], Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de médecine moléculaire (Im3), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fondation FondaMental [Créteil], The Institut Pasteur, INSERM, CNRS, University Denis Diderot Paris 7, ANR, Fondation FondaMentale, PHRC and Fondation Orange supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Candidate gene, Genetic Screens, Developmental and Pediatric Neurology, Pediatrics, Chromosomal Disorders, 0302 clinical medicine, Child, Genetics, Psychiatry, 0303 health sciences, education.field_of_study, Multidisciplinary, Chromosomal Deletions and Duplications, Pedigree, Mental Health, Neurology, Autism spectrum disorder, Medicine, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, Science, Population, Biology, Molecular Genetics, 03 medical and health sciences, Developmental Neuroscience, Genetic Mutation, Genetic variation, mental disorders, medicine, Humans, Genetic variability, education, Genetic Association Studies, 030304 developmental biology, Clinical Genetics, Genome, Human, Genetic Variation, Membrane Proteins, Human Genetics, medicine.disease, Genetics, Population, Asperger syndrome, Child Development Disorders, Pervasive, Case-Control Studies, Genetics of Disease, Autism, Human genome, Molecular Neuroscience, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16, Neuroscience
Abstract

Background: Autism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate. Methodology/Principal Findings: We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls. Conclusions/Significance: Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD.

Published
2011

9. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders

Author

Pauline Chaste, Mary Coleman, Marina Konyukh, Marion Leboyer, Roberto Toro, Fabien Fauchereau, Richard Delorme, Thomas Bourgeron, Christopher Gillberg, Claire S. Leblond, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation FondaMental [Créteil], Université Paris Diderot - Paris 7 (UPD7), Foundation for Autism Research, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Göteborgs Universitet (GU), Institute of Child Health [London], University College of London [London] (UCL), This work was supported by the Institut Pasteur, Université Denis Diderot Paris 7, the INSERM, the CNRS, the Fondation Orange, and the Fondation de France Fondation FondaMentale., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Gene Dosage, Biology, Affect (psychology), Gene dosage, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genetics, Pervasive developmental disorder, medicine, Animals, Homeostasis, Humans, Genetic Predisposition to Disease, Allele, Child, Gene, 030304 developmental biology, 0303 health sciences, medicine.disease, Developmental disorder, Child Development Disorders, Pervasive, Synapses, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, Function (biology)
Abstract

International audience; Autism spectrum disorders (ASD) are characterized by impairments in reciprocal social communication, and repetitive, stereotyped verbal and non-verbal behaviors. Genetic studies have provided a relatively large number of genes that constitute a comprehensive framework to better understand this complex and heterogeneous syndrome. Based on the most robust findings, three observations can be made. First, genetic contributions to ASD are highly heterogeneous and most probably involve a combination of alleles with low and high penetrance. Second, the majority of the mutations apparently affect a single allele, suggesting a key role for gene dosage in susceptibility to ASD. Finally, the broad expression and function of the causative genes suggest that alteration of synaptic homeostasis could be a common biological process associated with ASD. Understanding the mechanisms that regulate synaptic homeostasis should shed new light on the causes of ASD and could provide a means to modulate the severity of the symptoms.

Published
2010

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