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Human Molecular Genetics Advance Access published online on December 21, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm376
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Recurrent 16p11.2 microdeletions in autism

Ravinesh A. Kumar1, Samer KaraMohamed1, Jyotsna Sudi1, Donald F. Conrad1, Camille Brune5, Judith A. Badner4, T. Conrad Gilliam1, Norma J. Nowak6, Edwin H. Cook, Jr.5, William B. Dobyns1,2,3 and Susan L. Christian1,*

1 Departments of Human Genetics, University of Chicago, Chicago, IL 60637, USA 2 Departments of Neurology, University of Chicago, Chicago, IL 60637, USA 3 Departments of Pediatrics, University of Chicago, Chicago, IL 60637, USA 4 Departments of Psychiatry, University of Chicago, Chicago, IL 60637, USA 5 Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA 6 Roswell Park Cancer Institute, Department of Cancer Genetics; Buffalo, NY 14236, USA.

* Corresponding author: Susan L. Christian, Ph.D., Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 319, Chicago, IL 60637, Phone: 773-834-2971, Fax: 773-834-8470, Email: schrist{at}bsd.uchicago.edu

Received November 21, 2007; Revised December 19, 2007; Accepted December 19, 2007

Autism is a childhood neurodevelopmental disorder with a strong genetic component, yet the identification of autism susceptibility loci remains elusive. We investigated 180 autism probands and 372 control subjects by array comparative genomic hybridization (aCGH) using a 19K whole genome tiling path bacterial artificial chromosome (BAC) microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in 2 probands with autism and none in controls. The deletion spans ~500-kb and is flanked by ~147-kb segmental duplications (SDs) that are>99% identical, a common characteristic of genomic disorders. We assessed the frequency of this new autism genomic disorder by screening an additional 532 probands and 465 controls by quantitative PCR and identified 2 more patients but no controls with the microdeletion, indicating a combined frequency of 0.6% (4/712 autism versus 0/837 controls; Fisher exact test p-value = 0.044). We confirmed all 16p11.2 deletions using FISH, microsatellite analyses and aCGH, and mapped the approximate deletion breakpoints to the edges of the flanking SDs using a custom-designed high density oligonucleotide microarray. Bioinformatic analysis localized 12 of the 25 genes within the microdeletion to nodes in one interaction network. We performed phenotype analyses and found no striking features that distinguish patients with the 16p11.2 microdeletion as a distinct autism subtype. Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.


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