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

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 Délépine; Mark Lathrop; Dominique Bonneau; Vincent Guinchat; Françoise Devillard; Brigitte Assouline; Marie-Christine Mouren; Marion Leboyer; Christopher Gillberg; Tobias M. Boeckers; Thomas Bourgeron

doi:10.1371/journal.pgen.1002521

Journal Articles PLoS Genetics Year : 2012

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

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Claire S. Leblond

Function : Author

Génétique Humaine et Fonctions Cognitives

Jutta Heinrich

Function : Author

Universität Ulm - Ulm University [Ulm, Allemagne]

Richard Delorme

Function : Author

Génétique Humaine et Fonctions Cognitives

Service de psychopathologie de l'enfant et de l'adolescent

Christian Proepper

Function : Author

Universität Ulm - Ulm University [Ulm, Allemagne]

Catalina Betancur

Function : Author
PersonId : 13320
IdHAL : catalina-betancur
ORCID : 0000-0002-3327-4804
IdRef : 180835750

Physiopathologie des Maladies du Système Nerveux Central

Guillaume Huguet

Function : Author
PersonId : 768721
ORCID : 0000-0002-4746-6030

Génétique Humaine et Fonctions Cognitives

Marina Konyukh

Function : Author

Génétique Humaine et Fonctions Cognitives

Pauline Chaste

Function : Author

Génétique Humaine et Fonctions Cognitives

Elodie Ey

Function : Author
PersonId : 12550
IdHAL : elodie-ey
ORCID : 0000-0002-8202-3163
IdRef : 243636393

Génétique Humaine et Fonctions Cognitives

Maria Rastam

Function : Author

Department of Child and Adolescent Psychiatry

Henrik Anckarsäter

Function : Author

Forensic Psychiatry

Gudrun Nygren

Function : Author

Department of Child and Adolescent Psychiatry

I Carina Gillberg

Function : Author

Department of Child and Adolescent Psychiatry

Jonas Melke

Function : Author

Department of Pharmacology

Roberto Toro

Function : Author
PersonId : 172082
IdHAL : robertotoro
ORCID : 0000-0002-6671-858X
IdRef : 089439317

Génétique Humaine et Fonctions Cognitives

Beatrice Regnault

Function : Author

Génotypage des Eucaryotes (Plate-Forme)

Fabien Fauchereau

Function : Author

Génétique Humaine et Fonctions Cognitives

Oriane Mercati

Function : Author

Génétique Humaine et Fonctions Cognitives

Nathalie Lemière

Function : Author

Génétique Humaine et Fonctions Cognitives

David Skuse

Function : Author

Behavioural and Brain Sciences Unit, Institute of Child Health

Martin Poot

Function : Author

University Medical Center [Utrecht]

Richard Holt

Function : Author

The Wellcome Trust Centre for Human Genetics [Oxford]

Anthony P Monaco

Function : Author

The Wellcome Trust Centre for Human Genetics [Oxford]

Irma Järvelä

Function : Author

Department of Medical and Clinical Genetics [Helsinki]

Katri Kantojärvi

Function : Author

Department of Medical and Clinical Genetics [Helsinki]

Raija Vanhala

Function : Author

Department of Medical and Clinical Genetics [Helsinki]

Sarah Curran

Function : Author

Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry

David A. Collier

Function : Author

Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry

Social, Genetic and Developmental Psychiatry Centre

Patrick Bolton

Function : Author

Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry

Department of Child and Adolescent Psychiatry

Andreas Chiocchetti

Function : Author

Division of Molecular Genome Analysis

Sabine M. Klauck

Function : Author

Division of Molecular Genome Analysis

Fritz Poustka

Function : Author

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

Christine M. Freitag

Function : Author

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

Regina Waltes

Function : Author

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

Marnie Kopp

Function : Author

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

Eftichia Duketis

Function : Author

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

Elena Bacchelli

Function : Author

Department of Pharmacy and Biotechnology

Fiorella Minopoli

Function : Author

Department of Pharmacy and Biotechnology

Liliana Ruta

Function : Author

Institute of Biotechnology

Agatino Battaglia

Function : Author

Department of Psychiatry and Behavioral Sciences [Stanford]

Luigi Mazzone

Function : Author

Division of Child Neurology and Psychiatry, Department of Paediatrics

Elena Maestrini

Function : Author

Department of Pharmacy and Biotechnology

Ana F. Sequeira

Function : Author

Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]

BioFIG

Barbara Oliveira

Function : Author

Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]

Astrid Vicente

Function : Author

Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]

Guiomar Oliveira

Function : Author

Unidade de Neurodesenvolvimento e Autismo

Dalila Pinto

Function : Author

Human Genetics Center

Stephen W. Scherer

Function : Author

The Centre for Applied Genomics, Toronto

Program in Genetics and Genomic Biology

Diana Zelenika

Function : Author

Centre National de Génotypage

Marc Délépine

Function : Author
PersonId : 919144

Centre National de Génotypage

Mark Lathrop

Function : Author

Centre National de Génotypage

Dominique Bonneau

Function : Author

Centre Hospitalier Universitaire d'Angers

Biologie Neurovasculaire Intégrée

Vincent Guinchat

Function : Author

Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement

Françoise Devillard

Function : Author

Département de génétique et procréation

Brigitte Assouline

Function : Author

Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement

Marie-Christine Mouren

Function : Author

Service de psychopathologie de l'enfant et de l'adolescent

Marion Leboyer

Function : Author
PersonId : 756830
ORCID : 0000-0001-5473-3697
IdRef : 089352475

Institut Mondor de Recherche Biomédicale

Christopher Gillberg

Function : Author

Department of Child and Adolescent Psychiatry

Tobias M. Boeckers

Function : Author

Universität Ulm - Ulm University [Ulm, Allemagne]

Institute for Anatomy and Cell Biology

Thomas Bourgeron

Function : Correspondent author
PersonId : 747963
IdHAL : thomas-bourgeron
ORCID : 0000-0001-8164-9220
IdRef : 119761955

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Génétique Humaine et Fonctions Cognitives

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.

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Submitted on : Sunday, June 16, 2013-4:04:27 PM

Last modification on : Friday, March 24, 2023-2:52:57 PM

Long-term archiving on: Tuesday, September 17, 2013-4:17:29 AM

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inserm-00834560 , version 1 (16-06-2013)

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HAL Id : inserm-00834560 , version 1
DOI : 10.1371/journal.pgen.1002521
PUBMED : 22346768

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Claire S. Leblond, Jutta Heinrich, Richard Delorme, Christian Proepper, Catalina Betancur, et al.. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.. PLoS Genetics, 2012, 8 (2), pp.e1002521. ⟨10.1371/journal.pgen.1002521⟩. ⟨inserm-00834560⟩

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

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