Author
Listed:
- 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
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.Author Summary: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Mutations altering genes involved in the junction between brain cells have been repeatedly associated in ASD. For example, SHANK1, SHANK2 and SHANK3 emerged as one family of genes that are associated with ASD. However, little was known about the number of patients carrying these mutations and the clinical outcome. Here, we performed a new genetic screen of SHANK mutations and these results were analyzed in combination with those of the literature. In summary, SHANK mutations account for ∼1% of patients with ASD and were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment: 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. Given the high frequency and impact of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—this gene should be screened for mutations in clinical practice.
Suggested Citation
Claire S Leblond & Caroline Nava & Anne Polge & Julie Gauthier & Guillaume Huguet & Serge Lumbroso & Fabienne Giuliano & Coline Stordeur & Christel Depienne & Kevin Mouzat & Dalila Pinto & Jennifer Ho, 2014.
"Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments,"
PLOS Genetics, Public Library of Science, vol. 10(9), pages 1-15, September.
Handle:
RePEc:plo:pgen00:1004580
DOI: 10.1371/journal.pgen.1004580
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Cited by:
- Yueqi Wang & Simone Chiola & Guang Yang & Chad Russell & Celeste J. Armstrong & Yuanyuan Wu & Jay Spampanato & Paisley Tarboton & H. M. Arif Ullah & Nicolas U. Edgar & Amelia N. Chang & David A. Harmi, 2022.
"Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes,"
Nature Communications, Nature, vol. 13(1), pages 1-25, December.
- Myung Chung & Katsutoshi Imanaka & Ziyan Huang & Akiyuki Watarai & Mu-Yun Wang & Kentaro Tao & Hirotaka Ejima & Tomomi Aida & Guoping Feng & Teruhiro Okuyama, 2024.
"Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice,"
Nature Communications, Nature, vol. 15(1), pages 1-11, December.
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