title: SHANK1 Deletions in Males with Autism Spectrum Disorder.
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 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.
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.forename: Aparna
authors.initials: A
authors.lastname: Prasad
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.forename: Irene
authors.initials: I
authors.lastname: O'Connor
authors.forename: Carolyn
authors.initials: C
authors.lastname: Russell
authors.forename: Irene E
authors.initials: IE
authors.lastname: Drmic
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.forename: Ralph
authors.initials: R
authors.lastname: Roeth
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.forename: Guillaume
authors.initials: G
authors.lastname: Huguet
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.forename: Maria
authors.initials: M
authors.lastname: Rastam
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.forename: Evdokia
authors.initials: E
authors.lastname: Anagnostou
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.forename: Lonnie
authors.initials: L
authors.lastname: Zwaigenbaum
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Rappold
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000293:Adolescent; D000328:Adult; D002170:Canada; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005060:Europe; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D017384:Sequence Deletion; D013569:Synapses / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; C122162:SHANK2 protein, human