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Human Molecular Genetics Advance Access originally published online on December 21, 2007
Human Molecular Genetics 2008 17(4):628-638; doi:10.1093/hmg/ddm376
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© 2007 The Author(s)
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, Jr5, William B. Dobyns1,2,3 and Susan L. Christian1,*

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

* To whom correspondence should be addressed at: Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 319, Chicago, IL 60637, USA. Tel: +1 7738342971; Fax: +1 7738348470; Email: schrist{at}bsd.uchicago.edu

Received November 21, 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 microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in two 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 two 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 = 0.044). We confirmed all 16p11.2 deletions using fluorescence in situ hybridization, 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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