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SHANK1 Deletions in Males with Autism Spectrum Disorder

Sato, Daisuke; Lionel, Anath C.; Leblond, Claire S.; Prasad, Aparna; Pinto, Dalila; Walker, Susan; O'Connor, Irene; Russell, Carolyn; Drmic, Irene E. and Hamdan, Fadi F., et al. (2012) In American Journal of Human Genetics 90(5). p.879-887
Abstract
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... (More)
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. (Less)
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American Journal of Human Genetics
volume
90
issue
5
pages
879 - 887
publisher
Cell Press
external identifiers
  • wos:000303907500012
  • scopus:84860739976
ISSN
0002-9297
DOI
10.1016/j.ajhg.2012.03.017
language
English
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yes
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80b4604f-96bb-4963-b13b-e7fd9df9d709 (old id 2826555)
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2012-07-03 10:26:13
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@article{80b4604f-96bb-4963-b13b-e7fd9df9d709,
  abstract     = {Recent studies have highlighted the involvement of rare (&lt;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 &gt;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.},
  author       = {Sato, Daisuke and Lionel, Anath C. and Leblond, Claire S. and Prasad, Aparna and Pinto, Dalila and Walker, Susan and O'Connor, Irene and Russell, Carolyn and Drmic, Irene E. and Hamdan, Fadi F. and Michaud, Jacques L. and Endris, Volker and Roeth, Ralph and Delorme, Richard and Huguet, Guillaume and Leboyer, Marion and Råstam, Maria and Gillberg, Christopher and Lathrop, Mark and Stavropoulos, Dimitri J. and Anagnostou, Evdokia and Weksberg, Rosanna and Fombonne, Eric and Zwaigenbaum, Lonnie and Fernandez, Bridget A. and Roberts, Wendy and Rappold, Gudrun A. and Marshall, Christian R. and Bourgeron, Thomas and Szatmari, Peter and Scherer, Stephen W.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {5},
  pages        = {879--887},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {SHANK1 Deletions in Males with Autism Spectrum Disorder},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2012.03.017},
  volume       = {90},
  year         = {2012},
}