Journal Article

Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

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

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Proteins / Adaptor Proteins, Signal Transducing / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Adult / alpha7 Nicotinic Acetylcholine Receptor / Alternative Splicing / Alternative Splicing - genetics / Autism / Biology / Cell Line / Child / Child Development Disorders / Child Development Disorders, Pervasive / Child Development Disorders, Pervasive - genetics / Child, Preschool / Clinical Medicine / Cytology / Female / Gene Dosage / Gene Dosage - genetics / Gene Expression Regulation / Gene mutations / Genes / Genetic aspects / Genetics / Humans / Klinisk medicin / Life Sciences / Male / Medical and Health Sciences / Medical research / Medicin och hälsovetenskap / Medicine / Metabolism / Mutation / Nerve Tissue Proteins / Nerve Tissue Proteins - genetics / Neurons / Neurons - cytology / Nicotinic / Pathology / Pervasive / Physiological aspects / Preschool / Prevalence studies (Epidemiology) / Protein Isoforms / Protein Isoforms - genetics / Protein Isoforms - metabolism / Psychiatry / Psykiatri / Receptors / Receptors, Nicotinic / Receptors, Nicotinic - genetics / Receptors, Nicotinic - metabolism / Risk factors / RNA Splice Sites / RNA Splice Sites - genetics / Sequence Deletion / Sequence Deletion - genetics / Signal Transducing / Synapses / Synapses - genetics / Synapses - pathology / Tissue Distribution