Leblond, CS;
Heinrich, J;
Delorme, R;
Proepper, C;
Betancur, C;
Huguet, G;
Konyukh, M;
... Bourgeron, T; + view all
(2012)
Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders.
PLOS GENETICS
, 8
(2)
, Article ARTN e1002521. 10.1371/journal.pgen.1002521.
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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.
| Type: | Article |
|---|---|
| Title: | Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1002521 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1002521 |
| Language: | English |
| Additional information: | © 2012 Leblond et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Institut Pasteur, INSERM, APHP, ANR (ANR-08-MNPS-037-01—SynGen), Neuron-ERANET (EUHF-AUTISM), Fondation Orange, Fondation pour la Recherche Médicale, RTRS Santé Mentale (Foundation FondaMental), the Deutsche Forschungsgemeinschaft DFG (BO1718:3-1 and SFB497/B8), the Dutch Foundation for Brain Research (Hersenstichting, grant # 2008(1).34), and Wellcome Trust core grant (075491/Z/04). D Pinto is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (#213997). SW Scherer holds the GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1388232 |
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