TY - JOUR
T1 - SHANK1 deletions in males with autism spectrum disorder
AU - Sato, Daisuke
AU - Lionel, Anath C.
AU - Leblond, Claire S.
AU - Prasad, Aparna
AU - Pinto, Dalila
AU - Walker, Susan
AU - O'Connor, Irene
AU - Russell, Carolyn
AU - Drmic, Irene E.
AU - Hamdan, Fadi F.
AU - Michaud, Jacques L.
AU - Endris, Volker
AU - Roeth, Ralph
AU - Delorme, Richard
AU - Huguet, Guillaume
AU - Leboyer, Marion
AU - Rastam, Maria
AU - Gillberg, Christopher
AU - Lathrop, Mark
AU - Stavropoulos, Dimitri J.
AU - Anagnostou, Evdokia
AU - Weksberg, Rosanna
AU - Fombonne, Eric
AU - Zwaigenbaum, Lonnie
AU - Fernandez, Bridget A.
AU - Roberts, Wendy
AU - Rappold, Gudrun A.
AU - Marshall, Christian R.
AU - Bourgeron, Thomas
AU - Szatmari, Peter
AU - Scherer, Stephen W.
N1 - Funding Information:
This work was supported by grants from the University of Toronto McLaughlin Centre, NeuroDevNet, Genome Canada and the Ontario Genomics Institute, the Canadian Institutes for Health Research (CIHR), the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the government of Ontario, Autism Speaks, and The Hospital for Sick Children Foundation. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. G.A.R. was supported by Deutsche Forschungsgemeinschaft and the BMBF/NGFNplus (German Mental-Retardation Network). T.B. was supported by Agence Nationale de la Recherche (ANR-08-MNPS-037-01—SynGen), Neuron-ERANET (EUHF-AUTISM), and Fondation Orange. We are indebted to the individuals and their families for participating in this study and to The Centre for Applied Genomics at The Hospital for Sick Children. We thank A. Fiebig, A. Franke, and S. Schreiber at POPGEN (University of Kiel, Kiel, Germany), A. Stewart, R. McPherson, and R. Roberts of the University of Ottawa Heart Institute (University of Ottawa, Ottawa, Canada), the Wellcome Trust Case Control Consortium, and the Study of Addiction: Genetics and Environment consortium for providing control data. A provisional patent has been filed for The Hospital for Sick Children in S.W. Scherer's name.
PY - 2012/5/4
Y1 - 2012/5/4
N2 - Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers - but not female carriers - have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.
AB - Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers - but not female carriers - have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.
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U2 - 10.1016/j.ajhg.2012.03.017
DO - 10.1016/j.ajhg.2012.03.017
M3 - Article
C2 - 22503632
AN - SCOPUS:84860739976
SN - 0002-9297
VL - 90
SP - 879
EP - 887
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -