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1. 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

2. Impact of the gut microbiome on nicotine’s motivational effects and glial cells in the ventral tegmental area in male mice

Author

Alina Lakosa, Anaïs Rahimian, Flavio Tomasi, Fabio Marti, Lauren M. Reynolds, Léa Tochon, Vincent David, Anne Danckaert, Candice Canonne, Sylvana Tahraoui, Fabrice de Chaumont, Benoît Forget, Uwe Maskos, Morgane Besson, Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Plateforme technologique Bioimagerie Photonique - Photonic BioImaging Technologic Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by the Institut Pasteur, Paris (GPF Microbes and Brain, project 'µBIOTADDICT'). UtechS PBI/C2RT is part of the France BioImaging infrastructure supported by the French National Research Agency (ANR-10-INSB-04-01, 'Investments for the future') and is supported by Conseil de la Region Ile-de-France (Domaine d’Intérêt Majeur DIM1HEALTH) and by Fondation Française pour la Recherche Médicale (Programme Grands Equipements)., and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)

Subjects
Pharmacology, Psychiatry and Mental health, [SDV]Life Sciences [q-bio]
Abstract

International audience; A link between gut dysbiosis and the pathogenesis of brain disorders has been identified. A role for gut bacteria in drug reward and addiction has been suggested but very few studies have investigated their impact on brain and behavioral responses to addictive drugs so far. In particular, their influence on nicotine’s addiction-like processes remains unknown. In addition, evidence shows that glial cells shape the neuronal activity of the mesolimbic system but their regulation, within this system, by the gut microbiome is not established. We demonstrate that a lack of gut microbiota in male mice potentiates the nicotine-induced activation of sub-regions of the mesolimbic system. We further show that gut microbiota depletion enhances the response to nicotine of dopaminergic neurons of the posterior ventral tegmental area (pVTA), and alters nicotine’s rewarding and aversive effects in an intra-VTA self-administration procedure. These effects were not associated with gross behavioral alterations and the nicotine withdrawal syndrome was not impacted. We further show that depletion of the gut microbiome modulates the glial cells of the mesolimbic system. Notably, it increases the number of astrocytes selectively in the pVTA, and the expression of postsynaptic density protein 95 in both VTA sub-regions, without altering the density of the astrocytic glutamatergic transporter GLT1. Finally, we identify several sub-populations of microglia in the VTA that differ between its anterior and posterior sub-parts, and show that they are re-organized in conditions of gut microbiota depletion. The present study paves the way for refining our understanding of the pathophysiology of nicotine addiction.

Published
2023

3. Excitatory/inhibitory imbalance in autism: the role of glutamate and GABA gene-sets in symptoms and cortical brain structure

Author

Hollestein, Viola, Poelmans, Geert, Forde, Natalie J, Beckmann, Christian F, Ecker, Christine, Mann, Caroline, Schäfer, Tim, Moessnang, Carolin, Baumeister, Sarah, Banaschewski, Tobias, Bourgeron, Thomas, Loth, Eva, Dell'Acqua, Flavio, Murphy, Declan GM, Puts, Nicolaas A, Tillmann, Julian, Charman, Tony, Jones, Emily JH, Mason, Luke, Ambrosino, Sara, Holt, Rosemary, Bölte, Sven, Buitelaar, Jan K, Naaijen, Jilly, Hollestein, Viola [0000-0002-6326-4172], Poelmans, Geert [0000-0001-7039-6985], Banaschewski, Tobias [0000-0003-4595-1144], Loth, Eva [0000-0001-9458-9167], Murphy, Declan GM [0000-0002-6664-7451], Puts, Nicolaas A [0000-0003-1024-1927], Charman, Tony [0000-0003-1993-6549], Bölte, Sven [0000-0002-4579-4970], Buitelaar, Jan K [0000-0001-8288-7757], Apollo - University of Cambridge Repository, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Goethe-Universität Frankfurt am Main, King‘s College London, Universität Heidelberg [Heidelberg] = Heidelberg University, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Sackler Institute of Translational Neurodevelopment [London], F. Hoffmann-La Roche [Basel], University of London [London], Utrecht University [Utrecht], University of Cambridge [UK] (CAM), Karolinska Institutet [Stockholm], Curtin University [Perth], Planning and Transport Research Centre (PATREC), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], This work has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI, by the Horizon2020 supported programme CANDY Grant No. 847818 and a Veni grant from the Netherlands organization for scientific research (NWO) under grant number VI.Veni.194.032 awarded to JN. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the authors and not necessarily those of the funders., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), and European Project: 101069276,CANDY

Subjects
Adult, Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Autism Spectrum Disorder, article, Glutamic Acid, Brain, 692/699/476/1373, Cellular and Molecular Neuroscience, Psychiatry and Mental health, All institutes and research themes of the Radboud University Medical Center, 692/53, 59/57, Humans, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, 631/378, Transcriptome, gamma-Aminobutyric Acid, Biological Psychiatry
Abstract

Funder: AIMS-2TRIALS/EU-AIMS which receive support from Innovative Medicines Initiative Joint Undertaking grant numbers 115300 and 777394, Funder: Horizon2020 CANDY programme grant number 847818, Funder: Dutch NWO Veni grant grant number VI.Veni.194.032, The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods-combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6-30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.

Published
2023

4. Resting state EEG power spectrum and functional connectivity in autism: a cross-sectional analysis

Author

Garcés, Pilar, Baumeister, Sarah, Mason, Luke, Chatham, Christopher, Holiga, Stefan, Dukart, Juergen, Jones, Emily, Banaschewski, Tobias, Baron-Cohen, Simon, Bölte, Sven, Buitelaar, Jan, Durston, Sarah, Oranje, Bob, Persico, Antonio, Beckmann, Christian, Bougeron, Thomas, Dell’acqua, Flavio, Ecker, Christine, Moessnang, Carolin, Charman, Tony, Tillmann, Julian, Murphy, Declan, Johnson, Mark, Loth, Eva, Brandeis, Daniel, Hipp, Joerg, Ahmad, Jumana, Ambrosino, Sara, Auyeung, Bonnie, Bourgeron, Thomas, Bours, Carsten, Brammer, Michael, Brogna, Claudia, de Bruijn, Yvette, Chakrabarti, Bhismadev, Cornelissen, Ineke, Crawley, Daisy, Dumas, Guillaume, Faulkner, Jessica, Frouin, Vincent, Goyard, David, Ham, Lindsay, Hayward, Hannah, Holt, Rosemary, Kundu, Prantik, Lai, Meng-Chuan, Ardhuy, Xavier Liogier D’, Lombardo, Michael, Lythgoe, David, Mandl, René, Marquand, Andre, Mennes, Maarten, Meyer-Lindenberg, Andreas, Mueller, Nico, Oakley, Bethany, O’dwyer, Laurence, Oldehinkel, Marianne, Pandina, Gahan, Ruggeri, Barbara, Ruigrok, Amber, Sabet, Jessica, Sacco, Roberto, Cáceres, Antonia San José, Simonoff, Emily, Spooren, Will, Toro, Roberto, Tost, Heike, Waldman, Jack, Williams, Steve, Wooldridge, Caroline, Zwiers, Marcel, Leap Group, The Eu-Aims, Garcés, Pilar [0000-0003-4989-0123], Apollo - University of Cambridge Repository, Roche Innovation Center [Basel, Switzerland], Heidelberg University, University Hospital Mannheim | Universitätsmedizin Mannheim, University of London [London], Institute of Neuroscience and Medicine, Brain and Behaviour [Jülich, Germany] (INM-7), Jülich Research Centre, Autism Research Centre [Cambridge, Royaume-Uni], University of Cambridge [UK] (CAM), Centre for Psychiatry Research [Stockholm], Karolinska Institutet [Stockholm], Curtin University [Perth], Planning and Transport Research Centre (PATREC), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University Medical Center [Utrecht], Università degli Studi di Messina = University of Messina (UniMe), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), King‘s College London, Goethe-University Frankfurt am Main, Central Institute of Mental Health [Mannheim], This work was supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (grant FP7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions and from Autism Speaks. AIMS-2-TRIALS is funded by the Innovative Medicines Initiative 2 Joint Undertaking (IMI 2 JU) under grant agreement no. 777394. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program, EFPIA, Autism Speaks, Autistica, and SFARI. PG was supported by the Roche Postdoctoral Fellowship (RPF) program., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), and University of Zurich

Subjects
Adult, Adolescent, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Autism spectrum disorder, EEG, Resting state, Power spectrum, Functional connectivity, 610 Medicine & health, 1309 Developmental Biology, 2806 Developmental Neuroscience, 2738 Psychiatry and Mental Health, Developmental Neuroscience, 130 000 Cognitive Neurology & Memory, 1312 Molecular Biology, Humans, ddc:610, 10064 Neuroscience Center Zurich, Autistic Disorder, Child, Molecular Biology, Brain Mapping, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Research, 220 Statistical Imaging Neuroscience, Brain, Reproducibility of Results, Electroencephalography, 10058 Department of Child and Adolescent Psychiatry, Magnetic Resonance Imaging, Psychiatry and Mental health, Cross-Sectional Studies, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Developmental Biology
Abstract

Background Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. Methods We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2–32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants’ MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%–30% split). Results In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52–0.62, specificity 0.59–0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. Limitations The statistical power to detect weak effects—of the magnitude of those found in the training dataset—in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset’s effects. Conclusions This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects., Molecular Autism, 13

Published
2022

5. A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

Author

Mustafa Sahin, Jacob A. S. Vorstman, Delnaz Roshandel, Alana Iaboni, Iva Pritišanac, Richard Delorme, Stephen W. Scherer, Marjolaine Willems, Mehdi Zarrei, Lynette Lau, Jennifer L. Howe, Alan M. Moses, Evdokia Anagnostou, Brianna Godlewski, Livia O Loureiro, Miriam S. Reuter, Julie D. Forman-Kay, Anne-Claude Tabet, Siddharth Srivastava, Brett Trost, Suzanne M E Lewis, Christian R. Marshall, Olivia Rennie, Thomas W. Frazier, Peter Szatmari, Thomas Bourgeron, Elizabeth D. Buttermore, Kristina Calli, Stelios Georgiades, Amélie Piton, Dean Hartley, Clarrisa A Lisa Bradley, James Lespinasse, Serge Lumbroso, The Hospital for sick children [Toronto] (SickKids), Holland Bloorview Kids Rehabilitation Hospital [Toronto, ON, Canada], University of British Columbia (UBC), University of Toronto, Department of Biochemistry [University of Toronto], Harvard Medical School [Boston] (HMS), John Carroll University, McMaster University [Hamilton, Ontario], Centre for Addiction and Mental Health [Toronto] (CAMH), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Métropole Savoie [Chambéry], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), CHU Strasbourg, This work was funded by Autism Speaks, Autism Speaks Canada, the University of Toronto McLaughlin Centre, the Canada Foundation for Innovation, the Canadian Institutes of Health Research (CIHR), Genome Canada/Ontario Genomics Institute, the Government of Ontario, Brain Canada, Ontario Brain Institute Province of Ontario Neurodevelopmental Disorders (POND), and The Hospital for Sick Children Foundation. L.O.L holds Lap-Chee Tsui Postdoctoral Fellowship from The Hospital for Sick Children. S.W.S holds the Northbridge Chair in Paediatric Research at the Hospital for Sick Children and University of Toronto., and Retiveau, Nolwenn

Subjects
Proband, Genetic counseling, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, QH426-470, Biology, behavioral disciplines and activities, Article, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Genotype-phenotype distinction, mental disorders, Gene duplication, Genetics, medicine, Copy-number variation, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, medicine.disease, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, Medicine, Medical genomics, 030217 neurology & neurosurgery
Abstract

Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.

Published
2021

6. Fractionating autism based on neuroanatomical normative modeling

Author

Zabihi, Mariam, Floris, Dorothea L, Kia, Seyed Mostafa, Wolfers, Thomas, Tillmann, Julian, Arenas, Alberto Llera, Moessnang, Carolin, Banaschewski, Tobias, Holt, Rosemary, Baron-Cohen, Simon, Loth, Eva, Charman, Tony, Bourgeron, Thomas, Murphy, Declan, Ecker, Christine, Buitelaar, Jan K, Beckmann, Christian F, Marquand, Andre, EU-AIMS LEAP Group, Zabihi, Mariam [0000-0002-7083-2318], Kia, Seyed Mostafa [0000-0002-7128-814X], Banaschewski, Tobias [0000-0003-4595-1144], Charman, Tony [0000-0003-1993-6549], Murphy, Declan [0000-0002-6664-7451], Buitelaar, Jan K [0000-0001-8288-7757], Apollo - University of Cambridge Repository, TILT, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Radboud University Medical Center [Nijmegen], University of Oslo (UiO), Oslo University Hospital [Oslo], King‘s College London, University of Vienna [Vienna], Universität Heidelberg [Heidelberg], Medical Faculty [Mannheim], University of Cambridge [UK] (CAM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Goethe-Universität Frankfurt am Main, Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], University of Oxford [Oxford], The work is supported by the Netherlands Organization for Scientific Research VIDI Grant Nos. 016.156.415 (to A.F.M.) and 864.12.003 (to C.F.B.), European Union Seventh Framework Program Grant Nos. 602805 (AGGRESSOTYPE) (to J.K.B.), 603016 (MATRICS) (to J.K.B.), and 278948 (TACTICS) (to J.K.B.), European Community’s Horizon 2020 Program (H2020/2014–2020) Grant Nos. 643051 (MiND) (to J.K.B.) and 642996 (BRAINVIEW) (to J.K.B.), Wellcome Trust UK Strategic Award Grant No. 098369/Z/12/Z (to C.F.B.), and EU-AIMS (European Autism Interventions), which receives support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Program (Grant No. FP7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions and Innovative Medicines Initiative 2 Joint Undertaking Grant No. 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and AUTISM SPEAKS, Autistica, SFARI. D.M. was also supported by the NIHR Maudsley Biomedical Research Centre. S.B.-C. was funded by the Wellcome Trust and the Autism Research Trust during the period of this work., European Project: 602805,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,AGGRESSOTYPE(2013), European Project: 603016,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,MATRICS(2014), European Project: 278948,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,TACTICS(2012), European Project: 643051,H2020,H2020-MSCA-ITN-2014,MiND(2015), European Project: 642996,H2020,H2020-MSCA-ITN-2014,BRAINVIEW(2015), European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), Radboud University [Nijmegen], Universität Heidelberg [Heidelberg] = Heidelberg University, University Hospital Mannheim | Universitätsmedizin Mannheim, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Oxford, Buitelaar, Jan K. [0000-0001-8288-7757], and Baron-Cohen, Simon [0000-0001-9217-2544]

Subjects
Autism Spectrum Disorder, Autism, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], MESH: Magnetic Resonance Imaging, 0302 clinical medicine, Neurobiology, MESH: Child, Psychology, Young adult, Child, EU-AIMS LEAP Group, MESH: Autism Spectrum Disorder, Cortical Thickness, 0303 health sciences, 220 Statistical Imaging Neuroscience, Cognition, Autism spectrum disorders, MESH: Case-Control Studies, 692/699/476/1373, Magnetic Resonance Imaging, Psychiatry and Mental health, MESH: Young Adult, Autism spectrum disorder, 9, Female, Neurotypical, Clinical psychology, Adult, Adolescent, MESH: Autistic Disorder, Biology, Predictive markers, Article, lcsh:RC321-571, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, MESH: Neurobiology, 692/53/2423, Neurodevelopmental Condition, medicine, Humans, Autistic Disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, MESH: Adolescent, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MESH: Humans, [SCCO.NEUR]Cognitive science/Neuroscience, Case-control study, MESH: Adult, medicine.disease, Case-Control Studies, 59/57, Normative, Polygenic risk score, 631/477, MESH: Female, 030217 neurology & neurosurgery
Abstract

Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: SBC was funded by the Wellcome Trust and the Autism Research Trust during the period of this work., Funder: DM was supported by the NIHR Maudsley Biomedical Research Centre., Autism is a complex neurodevelopmental condition with substantial phenotypic, biological, and etiologic heterogeneity. It remains a challenge to identify biomarkers to stratify autism into replicable cognitive or biological subtypes. Here, we aim to introduce a novel methodological framework for parsing neuroanatomical subtypes within a large cohort of individuals with autism. We used cortical thickness (CT) in a large and well-characterized sample of 316 participants with autism (88 female, age mean: 17.2 ± 5.7) and 206 with neurotypical development (79 female, age mean: 17.5 ± 6.1) aged 6–31 years across six sites from the EU-AIMS multi-center Longitudinal European Autism Project. Five biologically based putative subtypes were derived using normative modeling of CT and spectral clustering. Three of these clusters showed relatively widespread decreased CT and two showed relatively increased CT. These subtypes showed morphometric differences from one another, providing a potential explanation for inconsistent case–control findings in autism, and loaded differentially and more strongly onto symptoms and polygenic risk, indicating a dilution of clinical effects across heterogeneous cohorts. Our results provide an important step towards parsing the heterogeneous neurobiology of autism.

Published
2020

7. Short rehabilitation training program may improve postural control in children with autism spectrum disorders: preliminary evidences

Author

Simona Caldani, Paola Atzori, Richard Delorme, Maria Pia Bucci, Hugo Peyre, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Pediatric Balance Evaluation center [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], High Functioning Autism Expert Centre [Paris], Fundamental Foundation [Paris], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
medicine.medical_specialty, Autism Spectrum Disorder, medicine.medical_treatment, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Posture, lcsh:Medicine, Severity of Illness Index, Article, Postural control, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Cognition, 0302 clinical medicine, Physical medicine and rehabilitation, Severity of illness, Postural Balance, Humans, Medicine, 0501 psychology and cognitive sciences, lcsh:Science, Child, Balance (ability), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Analysis of Variance, Multidisciplinary, Rehabilitation, business.industry, lcsh:R, 05 social sciences, medicine.disease, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Rehabilitation training, Autism, lcsh:Q, Psychiatric disorders, business, Neurological disorders, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

Autism Spectrum Disorders subjects (ASD) is characterized by postural control deficits. This study aimed to explore the effect of a short postural rehabilitation training program on postural capabilities in children with ASD. Two groups (G1 and G2) of twenty children with ASD of IQ-, sex- and age- matched (mean age 11.7 ± 2.4 years) were included in this study. Posture was recorded by using the Balance Quest from Framiral on unstable platform in three different viewing conditions. The rehabilitation program consisted in two distinct postural control training exercises. Postural recordings were performed twice at T1 and T2 for both groups of children. Between T1 and T2 a 6-minute postural training was performed by the G1 group only, while the G2 group had a 6-minute of rest. Children were allocated randomly to the G1 or G2 groups. At T1, postural instability was similar for both groups of ASD children (G1 and G2) desp+\ite viewing conditions. At T2, we observed an improvement of postural control related to a mixed effect of training rehabilitation but also of test-retest. Knowing the potential of new rehabilitation strategies, the impact of postural control deficit in ASD children needs to be reconsidered. Well design case-control studies are requested to ensure scientific validity of postural rehabilitation training program.

Published
2020

8. Increased risk of ADHD in families with ASD

Author

Manuel Bouvard, Hugo Peyre, Marion Leboyer, Richard Delorme, Céline Bouquet, Garry D. Honey, Anita Beggiato, Isabelle Scheid, Myriam Ly-Le Moal, Thomas Bourgeron, Marion Poumeyreau, Frédérique Amsellem, Anouck Amestoy, Federico Bolognani, Anna Maruani, Mathilde Septier, Alexandru Gaman, Psychiatrie de l'enfant et de l'adolescent [Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), 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), Centre hospitalier Charles Perrens [Bordeaux], Fondation FondaMental [Créteil], Roche Innovation Center [Basel, Switzerland], Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and The Institut Pasteur, INSERM, Fondation FondaMental, APHP, DHU Protect, Labex BioPsy and Fondation Orange supported this work

Subjects
Adult, Male, Parents, Proband, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, behavioral disciplines and activities, Gee, Young Adult, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Developmental and Educational Psychology, medicine, Child and adolescent psychiatry, Humans, Attention deficit hyperactivity disorder, Family, Genetic Predisposition to Disease, 0501 psychology and cognitive sciences, Sibling, Child, business.industry, Siblings, 05 social sciences, Family aggregation, General Medicine, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Attention Deficit Disorder with Hyperactivity, Autism spectrum disorder, Case-Control Studies, Child, Preschool, Pediatrics, Perinatology and Child Health, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, business, 050104 developmental & child psychology, Clinical psychology
Abstract

Attention Deficit and Hyperactive Disorder (ADHD) and Autism Spectrum Disorders (ASD) are frequent comorbid neurodevelopmental conditions and the overlap between both disorders remains to be delineated. A more complete understanding of the shared genetic and environmental factors is needed. Using a family-based method, we evaluated the risk of ADHD in a group of relatives with an ASD proband (ASD-) and a group of relatives with an ASD and ADHD proband (ASD+). We enrolled 1245 individuals in the study: 499 probands, their 746 first-degree relatives and 140 controls. We used a multivariate generalized estimating equation (GEE) model, in which the dependent variable was the ADHD diagnosis in the relatives and the independent variable the ASD+ or ASD- in probands. We adjusted for sociodemographic factors (age, sex, IQ) and for the nature of the familial relationship with the affected proband (parent or sibling). Among the probands, there were 287 ASD- and 212 ASD+ individuals. ADHD was more frequent in relatives (19%) than in the control group (7%) (p = 0.001). The risk of ADHD was higher in the ASD+ relatives group than in the ASD- relatives group (GEE model OR 1.58 [95% CI 1.04-2.38], p = 0.032). This result was found in parents (OR 1.96 [95% CI 1.14-3.36], but not in siblings (OR 1.28 [95% CI 0.84-1.94], p = 0.434). Our study provides a representative estimate of the family distribution of ADHD in relatives of ASD probands but supports the modest effect of shared genetic and environmental factors between both disorders.

Published
2018

9. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability

Author

Catherine Boileau, Anne Boland, Guillaume Jondeau, Mélodie Aubart, Jean-François Deleuze, Olivier Milleron, M. S. Gross, Steven Gazal, Nadine Hanna, Louise Benarroch, Marie-Paule Jacob, Emmanuelle Génin, Chantal Stheneur, Julien Buratti, Vincent Meyer, Thomas Bourgeron, Pauline Arnaud, Laurent Gouya, Isabelle Desguerre, Habib Zouali, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Gènes, Synapses et Cognition (CNRS - UMR3571 ), 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 d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Benarroch, Louise

Subjects
Adult, Collagen Type IV, Male, 0301 basic medicine, Marfan syndrome, Multifactorial Inheritance, Adolescent, Genetic Linkage, Fibrillin-1, [SDV]Life Sciences [q-bio], Quantitative Trait Loci, 030204 cardiovascular system & hematology, Biology, Thoracic aortic aneurysm, Article, Marfan Syndrome, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Genotype, Genetics, medicine, Humans, Cells, Cultured, Genetics (clinical), Exome sequencing, Aged, Genes, Modifier, Fibroblasts, Middle Aged, medicine.disease, Genetic architecture, [SDV] Life Sciences [q-bio], Phenotype, 030104 developmental biology, Mutation, Expression quantitative trait loci, Female, Age of onset
Abstract

International audience; Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.

Published
2018

10. Author Correction: A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author

Stephan Kemeny, Sandrine Passemard, Sandra Chantot-Bastaraud, Chloé Quélin, Laurence Perrin, Julien Buratti, Patrick Edery, Céline Dupont, Chantal Missirian, Philippe Vago, Alexandra Afenjar, Marie-Laure Vuillaume, Yline Capri, Klaus Dieterich, Laila El Khattabi, Charles Coutton, Françoise Devillard, Annick Toutain, Alain Verloes, Nicole Philip, Hubert Journel, Véronique Satre, Marie Ducloy, Delphine Héron, Richard Delorme, Cédric Le Caignec, Anne-Claude Tabet, Damien Sanlaville, Isabelle Marey, Laurence Faivre, Christèle Dubourg, Anne-Laure Mosca-Boidron, Laetitia Gouas, Abdelamdjid Benmansour, Jean Chiesa, Séverine Drunat, Cyril Mignot, Aurélia Jacquette, Boris Keren, Claire S. Leblond, Claire Beneteau, Brigitte Benzacken, Vincent Gatinois, Olivier Pichon, Damien Haye, Roberto Toro, Sandra Whalen, Dominique Martin, Thomas Rolland, Thomas Bourgeron, Albert David, Alexandre Mathieu, Mélanie Fradin, Frédérique Amsellem, Bertrand Isidor, James Lespinasse, Caroline Rooryck, Jacques Puechberty, Eva Pipiras, Lucile Pinson, Didier Lacombe, Jonathan M. Levy, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], CHU Trousseau [APHP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), CHU de Lyon, Centre Hospitalier Universitaire [Grenoble] (CHU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier de Chambéry (C.H.de Chambéry), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Le Mans (CH Le Mans), AP-HP Hôpital universitaire Robert-Debré [Paris], Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, UF de Cytogénétique, Institut Pasteur [Paris], Université de Bordeaux (UB), École normale supérieure - Rennes (ENS Rennes), Unité de Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Laboratoire Interdisciplinaire Carnot de Bourgogne (LICB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de génétique clinique [Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Service de Génétique, 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)-AP-HP Hôpital universitaire Robert-Debré [Paris], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Gatonero SA, Hôtel-Dieu de Nantes, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale, CHU Clermont-Ferrand-Hôpital d'Estaing, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des anomalies du développement [Lyon], UF de Biochimie et Génétique Moléculaire (BGM), CHU Grenoble, Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), IMAXIO, Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire Carémeau [Nîmes], Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Bretagne Atlantique [Vannes], Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Rolland, Thomas

Subjects
medicine.medical_specialty, lcsh:QH426-470, lcsh:Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, 0302 clinical medicine, Phelan-McDermid syndrome, Genetics, medicine, 0501 psychology and cognitive sciences, In patient, Clinical genetics, Author Correction, Psychiatry, Molecular Biology, Genetics (clinical), business.industry, lcsh:R, Neurodevelopmental disorders, 05 social sciences, lcsh:Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, business, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders., The underlying genetics of Phelan-McDermid syndrome Multiple chromosomal changes may impact the severity of symptoms in people with Phelan-McDermid syndrome (PMS). Thomas Bourgeron of the Institut Pasteur and colleagues in France conducted genomic analyses and explored the clinical features of 85 people with PMS, a condition caused by a deletion in the long arm of chromosome 22. It is often associated with severe symptoms such as intellectual disability, autism, and seizures. The chromosomal changes in 65% of those studied were not inherited. MRI brain scans showed visible abnormalities in 23 of 35 patients imaged. The size of the chromosomal deletion varied. Patients with small deletions were more likely to have autistic symptoms while those with large deletions were more likely to be unable to talk. The team also identified genes in chromosome 22 and in other regions of the genome that could modify the severity of PMS symptoms.

Published
2019

11. Reflections on a journey: a retrospective of the ISCB Student Council symposium series

Author

Benjamin A. Siranosian, R. Gonzalo Parra, Alexander Miguel Monzon, Julien Fumey, Dan DeBlasio, Sayane Shome, Mehedi Hassan, Farzana Rahman, Aishwarya Alex Namasivayam, Bart Cuypers, Nazeefa Fatima, University of South Wales (USW), University of Luxembourg [Luxembourg], Carnegie Mellon University [Pittsburgh] (CMU), Lund University [Lund], Stanford University, European Molecular Biology Laboratory [Heidelberg] (EMBL), Institute of Tropical Medicine [Antwerp] (ITM), University of Antwerp (UA), Iowa State University (ISU), Universidad Nacional de Quilmes (UNQ), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), and Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Young, Library science, Student Council, Community, Meeting Report, Development, lcsh:Computer applications to medicine. Medical informatics, Biochemistry, Networking, 03 medical and health sciences, Structural Biology, Research Support as Topic, Political science, Humans, Fellowships and Scholarships, Students, lcsh:QH301-705.5, Biology, Molecular Biology, Career, Computer. Automation, Symposium, Applied Mathematics, Publications, ISCB, Computational Biology, Congresses as Topic, Science Communication, Computer Science Applications, Chemistry, Leadership, 030104 developmental biology, lcsh:Biology (General), ECCB, lcsh:R858-859.7, ISMB, Engineering sciences. Technology, Mathematics, SCS
Abstract

International audience; This article describes the motivation, origin and evolution of the student symposia series organised by the ISCB Student Council. The meeting series started thirteen years ago in Madrid and has spread to four continents. The article concludes with the highlights of the most recent edition of annual Student Council Symposium held in conjunction with the 25th Conference on Intelligent Systems for Molecular Biology and the 16th European Conference on Computational Biology, in Prague, in July 2017.

Published
2018

12. Induced pluripotent stem cells as a tool to study brain circuits in autism-related disorders

Author

Aline Vitrac, Isabelle Cloëz-Tayarani, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The French Ministry of Education provided the funding for AV’s PhDs., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, Autism Spectrum Disorder, Autism, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Induced Pluripotent Stem Cells, Medicine (miscellaneous), Review, Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), lcsh:Biochemistry, Mice, 03 medical and health sciences, Neural Stem Cells, In vivo, medicine, Animals, Humans, lcsh:QD415-436, Progenitor cell, Induced pluripotent stem cell, Neurons, lcsh:R5-920, Transplantation, Developmental disorders, Brain, Cell Differentiation, Human induced pluripotent stem cells, Cell Biology, Human brain, Fibroblasts, medicine.disease, Phenotype, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Molecular Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Brain circuits, Nerve Net, Stem cell, lcsh:Medicine (General), Genetic Engineering, Neuroscience
Abstract

International audience; The mammalian brain is a very complex organ containing an estimated 200 billion cells in humans. Therefore, studying human brain development has become very challenging given all the data that are available from different approaches, notably genetic studies.Recent pluripotent stem cell methods have given rise to the possibility of modeling neurodevelopmental diseases associated with genetic defects. Fibroblasts from patients have been reprogrammed into pluripotent stem cells to derive appropriate neuronal lineages. They specifically include different subtypes of cortical neurons that are at the core of human-specific cognitive abilities. The use of neurons derived from induced pluripotent stem cells (iPSC) has led to deciphering convergent and pleiotropic neuronal synaptic phenotypes found in neurodevelopmental disorders such as autism spectrum disorders (ASD) and their associated syndromes. In addition to these initial studies, remarkable progress has been made in the field of stem cells, with the major objective of reproducing the in vivo maturation steps of human neurons. Recently, several studies have demonstrated the ability of human progenitors to respond to guidance cues and signals in vivo that can direct neurons to their appropriate sites of differentiation where they become fully mature neurons.We provide a brief overview on research using human iPSC in ASD and associated syndromes and on the current understanding of new theories using the re-implantation of neural precursors in mouse brain.

Published
2018

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