Novel Submicroscopic Chromosomal Abnormalities Detected in Autism Spectrum Disorder

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 p...

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Published in:	Biological psychiatry (1969) Vol. 63; no. 12; pp. 1111 - 1117
Main Authors:	Christian, Susan L, Brune, Camille W, Sudi, Jyotsna, Kumar, Ravinesh A, Liu, Shaung, Karamohamed, Samer, Badner, Judith A, Matsui, Seiichi, Conroy, Jeffrey, McQuaid, Devin, Gergel, James, Hatchwell, Eli, Gilliam, T. Conrad, Gershon, Elliot S, Nowak, Norma J, Dobyns, William B, Cook, Edwin H
Format:	Journal Article
Language:	English
Published:	New York, NY Elsevier Inc 15-06-2008 Elsevier Science
Subjects:	African Continental Ancestry Group - genetics Alleles Array comparative genomic hybridization autism Autistic Disorder - diagnosis Autistic Disorder - genetics Biological and medical sciences Child Child clinical studies Chromosome Aberrations Chromosome Deletion Chromosomes, Artificial, Bacterial - genetics Chromosomes, Human, Pair 15 - genetics Developmental disorders DNA Mutational Analysis European Continental Ancestry Group - genetics Female Gene Dosage - genetics Gene Duplication Genetic Predisposition to Disease - genetics Genetic Variation - genetics Genotype Humans Infantile autism Male Medical sciences microdeletions microduplications Nucleic Acid Hybridization - genetics Oligonucleotide Array Sequence Analysis Phenotype Polymerase Chain Reaction Psychiatry Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Array comparative genomic hybridization autism microdeletions microduplications Autism Pervasive developmental disorder Developmental disorder
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Summary:	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 ∼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.
ISSN:	0006-3223 1873-2402
DOI:	10.1016/j.biopsych.2008.01.009