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

Journal article
Authors Claire S Leblond
Caroline Nava
Anne Polge
Julie Gauthier
Guillaume Huguet
Serge Lumbroso
Fabienne Giuliano
Coline Stordeur
Christel Depienne
Kevin Mouzat
Dalila Pinto
Jennifer Howe
Nathalie Lemière
Christelle M Durand
Jessica Guibert
Elodie Ey
Roberto Toro
Hugo Peyre
Alexandre Mathieu
Frédérique Amsellem
Maria Rastam
I Carina Gillberg
Gudrun A Rappold
Richard Holt
Anthony P Monaco
Elena Maestrini
Pilar Galan
Delphine Heron
Aurélia Jacquette
Alexandra Afenjar
Agnès Rastetter
Alexis Brice
Françoise Devillard
Brigitte Assouline
Fanny Laffargue
James Lespinasse
Jean Chiesa
François Rivier
Dominique Bonneau
Beatrice Regnault
Diana Zelenika
Marc Delepine
Mark Lathrop
Damien Sanlaville
Caroline Schluth-Bolard
Patrick Edery
Laurence Perrin
Anne Claude Tabet
Michael J Schmeisser
Tobias M Boeckers
Mary Coleman
Daisuke Sato
Peter Szatmari
Stephen W Scherer
Guy A Rouleau
Catalina Betancur
Marion Leboyer
Christopher Gillberg
Richard Delorme
Thomas Bourgeron
Published in PLoS genetics
Volume 10
Issue 9
Pages e1004580
ISSN 1553-7404
Publication year 2014
Published at Gillberg Neuropsychiatry Centre
Pages e1004580
Language en
Subject categories Child and adolescent psychiatry


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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