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Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

Claire S. Leblond 1, 2 Caroline Nava 3 Anne Polge 4 Julie Gauthier 5 Guillaume Huguet 2, 1 Serge Lumbroso 4 Fabienne Giuliano 6 Coline Stordeur 2, 7, 1 Christel Depienne 3 Kevin Mouzat 4 Dalila Pinto 8 Jennifer Howe 9 Nathalie Lemière 2, 1 Christelle M. Durand 2, 1 Jessica Guibert 2, 1 Elodie Ey 2, 1 Roberto Toro 1, 2 Hugo Peyre 10 Alexandre Mathieu 2, 1 Frédérique Amsellem 2, 7, 11 Maria Rastam 12 Carina I. Gillberg 13 Gudrun A. Rappold 14 Richard Holt 15 Anthony P. Monaco 15 Elena Maestrini 16 Pilar Galan 17 Delphine Heron 18, 19 Aurélia Jacquette 18 Alexandra Afenjar 18, 19 Agnès Rastetter 3 Alexis Brice 3 Françoise Devillard 20 Brigitte Assouline 21 Fanny Laffargue 22 James Lespinasse 23 Jean Chiesa 24, 25 Francois Rivier 26, 27 Dominique Bonneau 28, 29 Beatrice Regnault 30 Diana Zelenika 31 Marc Délépine 31 Mark Lathrop 31 Damien Sanlaville 32 Caroline Schluth-Bolard 32 Patrick Edery 32 Laurence Perrin 33 Anne Claude Tabet 33 Michael J. Schmeisser 34 Tobias M. Boeckers 34 Mary Coleman 35 Daisuke Sato 9 Peter Szatmari 9 Stephen W. Scherer 9 Guy A. Rouleau 36 Catalina Betancur 37 Marion Leboyer 11, 38, 39 Christopher Gillberg 13, 40 Richard Delorme 2, 7, 11, 1 Thomas Bourgeron 2, 11, 1, * 
* Corresponding author
Abstract : SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
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Claire S. Leblond, Caroline Nava, Anne Polge, Julie Gauthier, Guillaume Huguet, et al.. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.. PLoS Genetics, Public Library of Science, 2014, 10 (9), pp.e1004580. ⟨10.1371/journal.pgen.1004580⟩. ⟨inserm-01061498⟩



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