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

Claire S. Leblond 1 Jutta Heinrich 2 Richard Delorme 1, 3 Christian Proepper 2 Catalina Betancur 4 Guillaume Huguet 1 Marina Konyukh 1 Pauline Chaste 1 Elodie Ey 1 Maria Rastam 5 Henrik Anckarsäter 6 Gudrun Nygren 7 I Carina Gillberg 7 Jonas Melke 8 Roberto Toro 1 Beatrice Regnault 9 Fabien Fauchereau 1 Oriane Mercati 1 Nathalie Lemière 1 David Skuse 10 Martin Poot 11 Richard Holt 12 Anthony P Monaco 12 Irma Järvelä 13 Katri Kantojärvi 13 Raija Vanhala 13 Sarah Curran 14 David A. Collier 14, 15 Patrick Bolton 14, 16 Andreas Chiocchetti 17 Sabine M. Klauck 18, 17 Fritz Poustka 19 Christine M. Freitag 19 Regina Waltes 19 Marnie Kopp 19 Eftichia Duketis 19 Elena Bacchelli 20 Fiorella Minopoli 20 Liliana Ruta 21 Agatino Battaglia 22 Luigi Mazzone 23 Elena Maestrini 20 Ana F. Sequeira 24, 25 Barbara Oliveira 24 Astrid Vicente 24 Guiomar Oliveira 26 Dalila Pinto 27 Stephen W. Scherer 28, 29 Diana Zelenika 30 Marc Délépine 30 Mark Lathrop 30 Dominique Bonneau 31, 32 Vincent Guinchat 33 Françoise Devillard 34 Brigitte Assouline 33 Marie-Christine Mouren 3 Marion Leboyer 35 Christopher Gillberg 7 Tobias M. Boeckers 2, 36 Thomas Bourgeron 1, * 
* Corresponding author
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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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, Public Library of Science, 2012, 8 (2), pp.e1002521. ⟨10.1371/journal.pgen.1002521⟩. ⟨inserm-00834560⟩



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