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

Leblond, Claire S.; Heinrich, Jutta; Delorme, Richard; Proepper, Christian; Betancur, Catalina; Huguet, Guillaume; Konyukh, Marina; Chaste, Pauline; Ey, Elodie and Råstam, Maria LU , et al. (2012) In PLoS Genetics 8(2).
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... (More)
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. (Less)
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2
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  • scopus:84859066832
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1553-7404
DOI
10.1371/journal.pgen.1002521
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English
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@article{48f13ffc-2109-40e9-9004-b0a835f24db6,
  abstract     = {Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model'' for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.},
  author       = {Leblond, Claire S. and Heinrich, Jutta and Delorme, Richard and Proepper, Christian and Betancur, Catalina and Huguet, Guillaume and Konyukh, Marina and Chaste, Pauline and Ey, Elodie and Råstam, Maria and Anckarsäter, Henrik and Nygren, Gudrun and Gillberg, I. Carina and Melke, Jonas and Toro, Roberto and Regnault, Beatrice and Fauchereau, Fabien and Mercati, Oriane and Lemiere, Nathalie and Skuse, David and Poot, Martin and Holt, Richard and Monaco, Anthony P. and Jarvela, Irma and Kantojarvi, Katri and Vanhala, Raija and Curran, Sarah and Collier, David A. and Bolton, Patrick and Chiocchetti, Andreas and Klauck, Sabine M. and Poustka, Fritz and Freitag, Christine M. and Waltes, Regina and Kopp, Marnie and Duketis, Eftichia and Bacchelli, Elena and Minopoli, Fiorella and Ruta, Liliana and Battaglia, Agatino and Mazzone, Luigi and Maestrini, Elena and Sequeira, Ana F. and Oliveira, Barbara and Vicente, Astrid and Oliveira, Guiomar and Pinto, Dalila and Scherer, Stephen W. and Zelenika, Diana and Delepine, Marc and Lathrop, Mark and Bonneau, Dominique and Guinchat, Vincent and Devillard, Francoise and Assouline, Brigitte and Mouren, Marie-Christine and Leboyer, Marion and Gillberg, Christopher and Boeckers, Tobias M. and Bourgeron, Thomas},
  issn         = {1553-7404},
  language     = {eng},
  number       = {2},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1002521},
  volume       = {8},
  year         = {2012},
}