title: Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.
abstract: SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.affiliation: INSERM U975 - CRICM, Institut du cerveau et de la moelle épinière (ICM), CNRS 7225 - CRICM, Hôpital Pitié-Salpêtrière, Paris, France; Sorbonne Universités, UPMC Univ Paris 6, Paris, France; UMR_S 975, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: Laboratoire de Biochimie, CHU Nîmes, Nîmes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Polge
authors.affiliation: Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Huguet
authors.affiliation: Laboratoire de Biochimie, CHU Nîmes, Nîmes, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Lumbroso
authors.affiliation: Department of Medical Genetics, Nice Teaching Hospital, Nice, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Giuliano
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France; Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France.
authors.forename: Coline
authors.initials: C
authors.lastname: Stordeur
authors.affiliation: INSERM U975 - CRICM, Institut du cerveau et de la moelle épinière (ICM), CNRS 7225 - CRICM, Hôpital Pitié-Salpêtrière, Paris, France; Sorbonne Universités, UPMC Univ Paris 6, Paris, France; UMR_S 975, Paris, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.affiliation: Laboratoire de Biochimie, CHU Nîmes, Nîmes, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mouzat
authors.affiliation: Departments of Psychiatry, Genetics and Genomic Sciences, Seaver Autism Center, The Mindich Child Health & Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Dalila
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authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children and the University of Toronto McLaughlin Centre, Toronto, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Howe
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lemière
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Christelle M
authors.initials: CM
authors.lastname: Durand
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Guibert
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Ey
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Toro
authors.affiliation: Laboratoire de Sciences Cognitives et Psycholinguistique, École Normale Supérieure, CNRS, EHESS, Paris, France.
authors.forename: Hugo
authors.initials: H
authors.lastname: Peyre
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mathieu
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France; FondaMental Foundation, Créteil, France.
authors.forename: Frédérique
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authors.affiliation: Department of Clinical Sciences in Lund, Lund University, Lund, Sweden.
authors.forename: Maria
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authors.lastname: Rastam
authors.affiliation: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
authors.forename: I Carina
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authors.affiliation: Department of Molecular Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Gudrun A
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Richard
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Anthony P
authors.initials: AP
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authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Elena
authors.initials: E
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authors.affiliation: Nutritional Epidemiology Research Unit, INSERM U557, INRA U1125, CNAM, University of Paris 13, CRNH IdF, Bobigny, France.
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authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité fonctionnelle de génétique clinique, Paris, France; Centre de Référence "Déficiences intellectuelles de causes rares", Paris, France and Groupe de Recherche Clinique "Déficience intellectuelle et autisme", UPMC, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, Service de Neuropédiatrie, Paris, France.
authors.forename: Delphine
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authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité fonctionnelle de génétique clinique, Paris, France; Centre de Référence "Déficiences intellectuelles de causes rares", Paris, France and Groupe de Recherche Clinique "Déficience intellectuelle et autisme", UPMC, Paris, France.
authors.forename: Aurélia
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authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité fonctionnelle de génétique clinique, Paris, France; Centre de Référence "Déficiences intellectuelles de causes rares", Paris, France and Groupe de Recherche Clinique "Déficience intellectuelle et autisme", UPMC, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, Service de Neuropédiatrie, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.affiliation: INSERM U975 - CRICM, Institut du cerveau et de la moelle épinière (ICM), CNRS 7225 - CRICM, Hôpital Pitié-Salpêtrière, Paris, France; Sorbonne Universités, UPMC Univ Paris 6, Paris, France; UMR_S 975, Paris, France.
authors.forename: Agnès
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authors.affiliation: INSERM U975 - CRICM, Institut du cerveau et de la moelle épinière (ICM), CNRS 7225 - CRICM, Hôpital Pitié-Salpêtrière, Paris, France; Sorbonne Universités, UPMC Univ Paris 6, Paris, France; UMR_S 975, Paris, France.
authors.forename: Alexis
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authors.affiliation: Département de génétique et procréation, Hôpital Couple-Enfant, Grenoble, France.
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authors.affiliation: UF de Cytogénétique et Génétique Médicale, Hôpital Caremeau, Nîmes, France.
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authors.affiliation: CHRU Montpellier, Neuropédiatrie CR Maladies Neuromusculaires, Montpellier, France; U1046, INSERM, Université Montpellier 1 et 2, Montpellier, France.
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authors.affiliation: LUNAM Université, INSERM U1083 et CNRS UMR 6214, Angers, France; Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France.
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authors.affiliation: Centre National de Génotypage, Evry, France.
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authors.forename: Damien
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authors.affiliation: Hospices Civils de Lyon, CHU de Lyon, Départment de Génétique, Centre de Recherche en Neurosciences de Lyon, CNRS UMR 5292, INSERM U1028, Claude Bernard Lyon I University, Bron, France.
authors.forename: Caroline
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authors.affiliation: Hospices Civils de Lyon, CHU de Lyon, Départment de Génétique, Centre de Recherche en Neurosciences de Lyon, CNRS UMR 5292, INSERM U1028, Claude Bernard Lyon I University, Bron, France.
authors.forename: Patrick
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authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Genetic department, Cytogenetic Unit, Paris, France.
authors.forename: Anne Claude
authors.initials: AC
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authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
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authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: Tobias M
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authors.affiliation: Foundation for Autism Research, Sarasota, Florida, United States of America.
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authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children and the University of Toronto McLaughlin Centre, Toronto, Canada.
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authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children and the University of Toronto McLaughlin Centre, Toronto, Canada.
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authors.initials: P
authors.lastname: Szatmari
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children and the University of Toronto McLaughlin Centre, Toronto, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Guy A
authors.initials: GA
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authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Paris, France; INSERM U1130, Paris, France; CNRS UMR 8246, Paris, France.
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.affiliation: FondaMental Foundation, Créteil, France; INSERM U955, Psychiatrie Génétique, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; Assistance Publique-Hôpitaux de Paris, DHU PePSY, Pôle de Psychiatrie et d'Addictologie des Hôpitaux Universitaires Henri Mondor, Créteil, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.affiliation: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden; Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France; Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France; FondaMental Foundation, Créteil, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France; FondaMental Foundation, Créteil, France.
authors.forename: Thomas
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mesh_terms: D016022:Case-Control Studies; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D013569:Synapses / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; C122162:SHANK2 protein, human