Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet

Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
Human Molecular Genetics (Impact Factor: 6.39). 03/2008; 17(4):628-38. DOI: 10.1093/hmg/ddm376
Source: PubMed


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 approximately 500-kb and is flanked by approximately 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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Available from: Norma J Nowak, Jan 08, 2014
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    • "Recurrent reciprocal deletions and duplications involving the 600 Kb 16p11.2 region were repeatedly associated with ASD and schizophrenia, but are characterized by a great phenotypic variability and low penetrance and do not segregate perfectly with ASD in multiplex families (Sanders et al. 2011; Depienne et al. 2009; Weiss et al. 2008; Kumar et al. 2008; Nava et al. 2014b; Levy et al. 2011). The 16p11.2 duplication by itself could then not be considered as the sole cause of ASD in this patient. "
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    • "It has been used to assess the functional biological networks and the candidate genes from the recurrent 16p11.2 microdeletions and the 1p34 microdeletion associated with autism [22,23]. "
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    • "Additionally, bearers of the 16p11.2 microdeletions and microduplications often develop autism (Kumar et al., 2008; Tabet et al., 2012). In such cases, the simple and complex diseases have been long suspected of sharing genetic architecture; whether there is a broader pattern of such associations, however, remains unclear. "
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