SHANK1 Deletions in Males with Autism Spectrum Disorder

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SHANK1 Deletions in Males with Autism Spectrum Disorder

Daisuke Sato et al.

The American Journal of Human Genetics (2012),

doi:10.1016/j.ajhg.2012.03.017

http://images.cell.com/images/EdImages/AJHG/ajhg1125_r.pdf

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 ¼ 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.