Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 81, Issue 6, 1289-1297, 1 December 2007
doi:10.1086/522590
Report
Contribution of SHANK3 Mutations to Autism Spectrum Disorder
Rainald Moessner*, a, b, Christian R. Marshall*, a, b, James S. Sutcliffee, Jennifer Skauga, b, Dalila Pintoa, b, John Vincentd, Lonnie Zwaigenbaumf, Bridget Fernandezg, Wendy Robertsc, Peter Szatmarih and Stephen W. Scherera, b, 
, 
a Centre for Applied Genomics, University of Toronto, Toronto
b Program in Genetics and Genome Biology, University of Toronto, Toronto
c Autism Research Unit, University of Toronto, Toronto
d Hospital for Sick Children, and Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry, University of Toronto, Toronto
e Center for Molecular Neuroscience and Vanderbilt Kennedy Center, Vanderbilt University, Nashville
f Department of Pediatrics, University of Alberta, Edmonton
g Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John’s
h Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada
Address for correspondence and reprints: Dr. Stephen W. Scherer, The Centre for Applied Genomics, The Hospital for Sick Children, 14th Floor, Toronto Medical Discovery Tower, MaRS Discovery District, 101 College Street, Room 14-701, Toronto, Ontario M5G 1L7, Canada* These two authors contributed equally to this work.
Abstract
Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.
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