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

Claire 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 Durand; Jessica Guibert; Elodie Ey; Roberto Toro; Hugo Peyre; Alexandre Mathieu; Frédérique Amsellem; Maria Rastam; Carina Gillberg; Gudrun Rappold; Richard Holt; Anthony 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; Francois Rivier; Dominique Bonneau; Beatrice Regnault; Diana Zelenika; Marc Délépine; Mark Lathrop; Damien Sanlaville; Caroline Schluth-Bolard; Patrick Edery; Laurence Perrin; Anne Claude Tabet; Michael Schmeisser; Tobias Boeckers; Mary Coleman; Daisuke Sato; Peter Szatmari; Stephen Scherer; Guy Rouleau; Catalina Betancur; Marion Leboyer; Christopher Gillberg; Richard Delorme; Thomas Bourgeron

doi:10.1371/journal.pgen.1004580

Journal articles

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

Claire 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 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 Gillberg ¹³ Gudrun Rappold ¹⁴ Richard Holt ¹⁵ Anthony 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 Francois Rivier ^{25, 26} Dominique Bonneau ^{27, 28} Beatrice Regnault ²⁹ Diana Zelenika ³⁰ Marc Délépine ³⁰ Mark Lathrop ³⁰ Damien Sanlaville ³¹ Caroline Schluth-Bolard ³¹ Patrick Edery ³¹ Laurence Perrin ³² Anne Claude Tabet ³² Michael Schmeisser ³³ Tobias Boeckers ³³ Mary Coleman ³⁴ Daisuke Sato ⁹ Peter Szatmari ⁹ Stephen Scherer ⁹ Guy Rouleau ³⁵ Catalina Betancur ³⁶ Marion Leboyer ^{11, 37, 38} Christopher Gillberg ^{13, 39} Richard Delorme ^{2, 7, 11, 1} Thomas Bourgeron ^{2, 11, 1, *}

* Corresponding author

1 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions

2 Gènes, Synapses et Cognition

3 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière

4 Service de Biochimie

5 Laboratoire de diagnotic moléculaire

6 Service de génétique médicale

7 Service de Psychiatrie de l'Enfant et de l'Adolescent

8 Departments of Psychiatry, Genetics and Genomic Sciences

9 Program in Genetics and Genomic Biology

10 LSCP - Laboratoire de sciences cognitives et psycholinguistique

11 Fondation FondaMental [Créteil]

12 Department of Clinical Sciences

13 Gillberg Neuropsychiatry Centre [Göteborg, Sueden]

14 Department of Molecular Human Genetics

15 The Wellcome Trust Centre for Human Genetics [Oxford]

16 Department of Pharmacy and Biotechnology

17 UREN - Unité de Recherche en Epidémiologie Nutritionnelle

18 Unité Fonctionnelle de Génétique Clinique

19 Service de Neuropédiatrie

20 Département de génétique et procréation

21 Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement

22 Service de Génétique Médical

23 Département de Génétique Chromosomique

24 Laboratoire de Cytogénétique

25 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]

26 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]

27 BNMI - Biologie Neurovasculaire et Mitochondriale Intégrée

28 Service de Biochimie et Génétique

29 Génotypage des Eucaryotes (Plate-Forme)

30 CNG - Centre National de Génotypage

31 CRNL - Centre de recherche en neurosciences de Lyon

32 Département de génétique

33 Institut for Anatomy and Cell Biology

34 Foundation for Autism Research

35 Center of Excellence in Neuroscience

36 NPS - Neurosciences Paris Seine

37 IMRB - Institut Mondor de Recherche Biomédicale

38 Service de psychiatrie

39 Institute of Child Health

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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Journal articles

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Life Sciences [q-bio] / Genetics

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

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

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