Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Claire S. Leblond; Jutta Heinrich; Richard Delorme; Christian Proepper; Catalina Betancur; Guillaume Huguet; Marina Konyukh; Pauline Chaste; Elodie Ey; Maria Rastam; Henrik Anckarsater; Gudrun Nygren; I. Carina Gillberg; Jonas Melke; Roberto Toro; Beatrice Regnault; Fabien Fauchereau; Oriane Mercati; Nathalie Lemiere; David Skuse; Martin Poot; Richard Holt; Anthony P. Monaco; Irma Jarvela; Katri Kantojarvi; Raija Vanhala; Sarah Curran; David A. Collier; Patrick Bolton; Andreas Chiocchetti; Sabine M. Klauck; Fritz Poustka; Christine M. Freitag; Regina Waltes; Marnie Kopp; Eftichia Duketis; Elena Bacchelli; Fiorella Minopoli; Liliana Ruta; Agatino Battaglia; Luigi Mazzone; Elena Maestrini; Ana F. Sequeira; Barbara Oliveira; Astrid Vicente; Guiomar Oliveira; Dalila Pinto; Stephen W. Scherer; Diana Zelenika; Marc Delepine; Mark Lathrop; Dominique Bonneau; Vincent Guinchat; Francoise Devillard; Brigitte Assouline; Marie-Christine Mouren; Marion Leboyer; Christopher Gillberg; Tobias M. Boeckers; Thomas Bourgeron

doi:10.1371/journal.pgen.1002521

Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Claire S. Leblond, Jutta Heinrich, Richard Delorme, Christian Proepper, Catalina Betancur, Guillaume Huguet, Marina Konyukh, Pauline Chaste, Elodie Ey, Maria Rastam, Henrik Anckarsater, Gudrun Nygren, I. Carina Gillberg, Jonas Melke, Roberto Toro, Beatrice Regnault, Fabien Fauchereau, Oriane Mercati, Nathalie Lemiere, David SkuseMartin Poot, Richard Holt, Anthony P. Monaco, Irma Jarvela, Katri Kantojarvi, Raija Vanhala, Sarah Curran, David A. Collier, Patrick Bolton, Andreas Chiocchetti, Sabine M. Klauck, Fritz Poustka, Christine M. Freitag, Regina Waltes, Marnie Kopp, Eftichia Duketis, Elena Bacchelli, Fiorella Minopoli, Liliana Ruta, Agatino Battaglia, Luigi Mazzone, Elena Maestrini, Ana F. Sequeira, Barbara Oliveira, Astrid Vicente, Guiomar Oliveira, Dalila Pinto, Stephen W. Scherer, Diana Zelenika, Marc Delepine, Mark Lathrop, Dominique Bonneau, Vincent Guinchat, Francoise Devillard, Brigitte Assouline, Marie-Christine Mouren, Marion Leboyer, Christopher Gillberg, Tobias M. Boeckers, Thomas Bourgeron

Research output: Contribution to journal › Article › peer-review

343 Citations (Scopus)

226 Downloads (Pure)

Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model'' for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Original language	English
Article number	e1002521
Journal	PL o S Genetics
Volume	8
Issue number	2
DOIs	https://doi.org/10.1371/journal.pgen.1002521
Publication status	Published - 9 Feb 2012

Access to Document

10.1371/journal.pgen.1002521

Leblond et al 2013
© 2012 Leblond et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Final published version, 1.05 MB

Cite this

Leblond, C. S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., Konyukh, M., Chaste, P., Ey, E., Rastam, M., Anckarsater, H., Nygren, G., Gillberg, I. C., Melke, J., Toro, R., Regnault, B., Fauchereau, F., Mercati, O., Lemiere, N., ... Bourgeron, T. (2012). Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders. PL o S Genetics, 8(2), Article e1002521. https://doi.org/10.1371/journal.pgen.1002521

@article{2af61bb701dd4de18bd90b9acabd8041,

title = "Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders",

abstract = "Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the {"}multiple hit model'' for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.",

author = "Leblond, {Claire S.} and Jutta Heinrich and Richard Delorme and Christian Proepper and Catalina Betancur and Guillaume Huguet and Marina Konyukh and Pauline Chaste and Elodie Ey and Maria Rastam and Henrik Anckarsater and Gudrun Nygren and Gillberg, {I. Carina} and Jonas Melke and Roberto Toro and Beatrice Regnault and Fabien Fauchereau and Oriane Mercati and Nathalie Lemiere and David Skuse and Martin Poot and Richard Holt and Monaco, {Anthony P.} and Irma Jarvela and Katri Kantojarvi and Raija Vanhala and Sarah Curran and Collier, {David A.} and Patrick Bolton and Andreas Chiocchetti and Klauck, {Sabine M.} and Fritz Poustka and Freitag, {Christine M.} and Regina Waltes and Marnie Kopp and Eftichia Duketis and Elena Bacchelli and Fiorella Minopoli and Liliana Ruta and Agatino Battaglia and Luigi Mazzone and Elena Maestrini and Sequeira, {Ana F.} and Barbara Oliveira and Astrid Vicente and Guiomar Oliveira and Dalila Pinto and Scherer, {Stephen W.} and Diana Zelenika and Marc Delepine and Mark Lathrop and Dominique Bonneau and Vincent Guinchat and Francoise Devillard and Brigitte Assouline and Marie-Christine Mouren and Marion Leboyer and Christopher Gillberg and Boeckers, {Tobias M.} and Thomas Bourgeron",

year = "2012",

month = feb,

day = "9",

doi = "10.1371/journal.pgen.1002521",

language = "English",

volume = "8",

journal = "PL o S Genetics",

issn = "1553-7404",

publisher = "Public Library of Science",

number = "2",

}

Leblond, CS, Heinrich, J, Delorme, R, Proepper, C, Betancur, C, Huguet, G, Konyukh, M, Chaste, P, Ey, E, Rastam, M, Anckarsater, H, Nygren, G, Gillberg, IC, Melke, J, Toro, R, Regnault, B, Fauchereau, F, Mercati, O, Lemiere, N, Skuse, D, Poot, M, Holt, R, Monaco, AP, Jarvela, I, Kantojarvi, K, Vanhala, R, Curran, S , Collier, DA , Bolton, P, Chiocchetti, A, Klauck, SM, Poustka, F, Freitag, CM, Waltes, R, Kopp, M, Duketis, E, Bacchelli, E, Minopoli, F, Ruta, L, Battaglia, A, Mazzone, L, Maestrini, E, Sequeira, AF, Oliveira, B, Vicente, A, Oliveira, G, Pinto, D, Scherer, SW, Zelenika, D, Delepine, M, Lathrop, M, Bonneau, D, Guinchat, V, Devillard, F, Assouline, B, Mouren, M-C, Leboyer, M, Gillberg, C, Boeckers, TM & Bourgeron, T 2012, 'Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders', PL o S Genetics, vol. 8, no. 2, e1002521. https://doi.org/10.1371/journal.pgen.1002521

TY - JOUR

T1 - Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

AU - Leblond, Claire S.

AU - Heinrich, Jutta

AU - Delorme, Richard

AU - Proepper, Christian

AU - Betancur, Catalina

AU - Huguet, Guillaume

AU - Konyukh, Marina

AU - Chaste, Pauline

AU - Ey, Elodie

AU - Rastam, Maria

AU - Anckarsater, Henrik

AU - Nygren, Gudrun

AU - Gillberg, I. Carina

AU - Melke, Jonas

AU - Toro, Roberto

AU - Regnault, Beatrice

AU - Fauchereau, Fabien

AU - Mercati, Oriane

AU - Lemiere, Nathalie

AU - Skuse, David

AU - Poot, Martin

AU - Holt, Richard

AU - Monaco, Anthony P.

AU - Jarvela, Irma

AU - Kantojarvi, Katri

AU - Vanhala, Raija

AU - Curran, Sarah

AU - Collier, David A.

AU - Bolton, Patrick

AU - Chiocchetti, Andreas

AU - Klauck, Sabine M.

AU - Poustka, Fritz

AU - Freitag, Christine M.

AU - Waltes, Regina

AU - Kopp, Marnie

AU - Duketis, Eftichia

AU - Bacchelli, Elena

AU - Minopoli, Fiorella

AU - Ruta, Liliana

AU - Battaglia, Agatino

AU - Mazzone, Luigi

AU - Maestrini, Elena

AU - Sequeira, Ana F.

AU - Oliveira, Barbara

AU - Vicente, Astrid

AU - Oliveira, Guiomar

AU - Pinto, Dalila

AU - Scherer, Stephen W.

AU - Zelenika, Diana

AU - Delepine, Marc

AU - Lathrop, Mark

AU - Bonneau, Dominique

AU - Guinchat, Vincent

AU - Devillard, Francoise

AU - Assouline, Brigitte

AU - Mouren, Marie-Christine

AU - Leboyer, Marion

AU - Gillberg, Christopher

AU - Boeckers, Tobias M.

AU - Bourgeron, Thomas

PY - 2012/2/9

Y1 - 2012/2/9

N2 - Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model'' for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

AB - Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model'' for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

U2 - 10.1371/journal.pgen.1002521

DO - 10.1371/journal.pgen.1002521

M3 - Article

SN - 1553-7404

VL - 8

JO - PL o S Genetics

JF - PL o S Genetics

IS - 2

M1 - e1002521

ER -

Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Abstract

Access to Document

Fingerprint

Cite this