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

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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.


  • Claire S. Leblond
  • Jutta Heinrich
  • Richard Delorme
  • Christian Proepper
  • Catalina Betancur
  • Guillaume Huguet
  • Marina Konyukh
  • Pauline Chaste
  • Elodie Ey
  • Henrik Anckarsäter
  • 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
Enheter & grupper

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Psykiatri
TidskriftPLoS Genetics
StatusPublished - 2012
Peer review utfördJa


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