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 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.
Christian
Susan L
SL
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. schrist@bsd.uchicago.edu
Brune
Camille W
CW
Sudi
Jyotsna
J
Kumar
Ravinesh A
RA
Liu
Shaung
S
Karamohamed
Samer
S
Badner
Judith A
JA
Matsui
Seiichi
S
Conroy
Jeffrey
J
McQuaid
Devin
D
Gergel
James
J
Hatchwell
Eli
E
Gilliam
T Conrad
TC
Gershon
Elliot S
ES
Nowak
Norma J
NJ
Dobyns
William B
WB
Cook
Edwin H
EH
D000483:Alleles; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D044383:Black People / Q000235:genetics; D002648:Child; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D009693:Nucleic Acid Hybridization / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D044465:White People / Q000235:genetics