Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation

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Using microarrays, we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation. DNA sequencing of SHANK2 in 396 individuals with ASD, 184 individuals with mental retardation and 659 unaffected individuals (controls) revealed additional variants that were specific to ASD and mental retardation cases, including a de novo nonsense mutation and seven rare inherited changes. Our findings further link common genes between ASD and intellectual disability.

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Figure 1: Microdeletions and mutations of SHANK2 in mental retardation and ASD.

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Gene Expression Omnibus


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We gratefully thank E. Fenner, M. Fritsche and S. Peykov for sequencing and technical support, and we thank all the affected individuals' families for their cooperation. We thank A. Fiebig, A. Franke and S. Schreiber at POPGEN (University of Kiel, Kiel, Germany) and A. Stewart, R. McPherson and R. Roberts of the University of Ottawa Heart Institute (University of Ottawa, Ottawa, Canada) for generously providing population control microarray data. The international Autism Genome Project and Autism Speaks is also gratefully acknowledged for support. Funding was provided by the German Mental Retardation Network (MRNET), supported by the Federal Ministry of Education and Research, Germany, by the Deutsche Forschungsgesellschaft (DFG; SFB488) and the Medical Faculty of Heidelberg. S.B. was funded by a fellowship of CellNetworks–Cluster of Excellence (EXC81) and is a member of Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS). S.W.S. is supported by The Centre for Applied Genomics, Genome Canada and Ontario Genomics Institute, the Canadian Institutes for Health Research (CIHR), the Canadian Institute for Advanced Research (CIFAR), the McLaughlin Centre, the Canada Foundation for Innovation, the Ontario Ministry of Research and Innovation and the Hospital for Sick Children Foundation. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children. G.A.R. is a member of CellNetworks–Cluster of Excellence (EXC81). Dedicated to Mrs. Elisabeth Berkel.

Author information

S.B. performed the majority of the experiments, designed the figures and contributed to the manuscript. C.R.M., D.P. and M.B. carried out array analyses. S.B. and C.R.M. performed breakpoint mapping. B.W., J.H., R.R. and V.E. performed sequencing and FISH analysis. R.S. contributed to the experimental design. U.M., W.R., P.S., H.E. and A.R. provided case material and clinical information. All co-authors commented on the manuscript. G.A.R. conceived and directed the study. Data interpretation and writing of the manuscript was carried out by S.W.S. and G.A.R.

Correspondence to Gudrun A Rappold.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4, Supplementary Tables 1–3 and Supplementary Methods (PDF 1636 kb)

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Berkel, S., Marshall, C., Weiss, B. et al. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet 42, 489–491 (2010) doi:10.1038/ng.589

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