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. 2008 Jun 15;63(12):1111-7.
doi: 10.1016/j.biopsych.2008.01.009. Epub 2008 Mar 28.

Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder

Susan L Christian  1 , Camille W Brune, Jyotsna Sudi, Ravinesh A Kumar, Shaung Liu, Samer Karamohamed, Judith A Badner, Seiichi Matsui, Jeffrey Conroy, Devin McQuaid, James Gergel, Eli Hatchwell, T Conrad Gilliam, Elliot S Gershon, Norma J Nowak, William B Dobyns, Edwin H Cook Jr
Affiliations

Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder

Susan L Christian et al. Biol Psychiatry. .

Abstract

Background: One genetic mechanism known to be associated with autism spectrum disorders (ASD) is chromosomal abnormalities. The identification of copy number variants (CNV), i.e., microdeletions and microduplications that are undetectable at the level of traditional cytogenetic analysis, allows the potential association of submicroscopic chromosomal imbalances and human disease.

Methods: We performed array comparative genomic hybridization (aCGH) utilizing a 19K whole genome tiling path bacterial artificial chromosome (BAC) microarray on 397 unrelated subjects with autism spectrum disorder. Common CNV were excluded using a control group comprised of 372 individuals from the National Institute of Mental Health (NIMH) Genetics Initiative Control samples. Confirmation studies were performed on all remaining CNV using fluorescence in situ hybridization (FISH), microsatellite analysis, and/or quantitative polymerase chain reaction (PCR) analysis.

Results: A total of 51 CNV were confirmed in 46 ASD subjects. Three maternal interstitial duplications of 15q11-q13 known to be associated with ASD were identified. The other 48 CNV ranged in size from 189 kilobase (kb) to 5.5 megabase (Mb) and contained from 0 to approximately 40 National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) genes. Seven CNV were de novo and 44 were inherited.

Conclusions: Fifty-one autism-specific CNV were identified in 46 of 397 ASD patients using a 19K BAC microarray for an overall rate of 11.6%. These microdeletions and microduplications cause gene dosage imbalance in 272 genes, many of which could be considered as candidate genes for autism.

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Conflict of interest statement

Financial disclosures and conflicts of interest

Susan L. Christian reported no biomedical interests or potential conflicts of interest. Camille W. Brune reported no biomedical interests or potential conflicts of interest. Jyotsna Sudi reported no biomedical interests or potential conflicts of interest. Ravinesh A. Kumar reported no biomedical interests or potential conflicts of interest. Shaung Liu reported no biomedical interests or potential conflicts of interest. Samer KaraMohamed reported no biomedical interests or potential conflicts of interest. Judith A. Badner reported no biomedical interests or potential conflicts of interest. Seiichi Matsui reported no biomedical interests or potential conflicts of interest. Jeffrey Conroy reported no biomedical interests or potential conflicts of interest. Devin McQuaid reported no biomedical interests or potential conflicts of interest. James Gergel reported no biomedical interests or potential conflicts of interest. Eli Hatchwell reported no biomedical interests or potential conflicts of interest. T. Conrad Gilliam reported no biomedical interests or potential conflicts of interest. Elliot S. Gershon reports that he is a consultant to Epix Pharmaceuticals, which has no interest in these findings. Norma J. Nowak reported no biomedical interests or potential conflicts of interest. William B. Dobyns reported no biomedical interests or potential conflicts of interest. Edwin H. Cook, Jr reported no biomedical interests or potential conflicts of interest.

Figures

Figure 1
Figure 1. Duplication 2p15 aCGH results
The aCGH results show the log2 ratio of the patient vs. reference DNA on the vertical axis. Each individual BAC is represented as a single blue dot and the horizontal axis shows the position of each BAC along chromosome 2. The duplication of 2p15 is indicated by an arrow pointing to a vertical line of dots.
Figure 2
Figure 2. Duplication 2p15 FISH results
The proximal breakpoint boundary is demonstrated where RP11-662L16 (green) shows 2 normal signals while RP11-270B14 (red) shows a larger signal on one metaphase chromosome and an extra signal in the interphase nucleus.
Figure 3
Figure 3. Deletion 17p12 aCGH results
In this case the arrow indicates a cluster of dots, located between −0.5 and −1.0, that identifies the deletion.
Figure 4
Figure 4. Deletion 17p12 FISH results
The distal breakpoint boundary is demonstrated where RP11-668O24 (green) shows 2 normal signals while RP11-465O5 (red) shows a single signal in both the metaphase chromosomes and the interphase nucleus.
See this image and copyright information in PMC

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