Association between microdeletion and microduplication at 16p11.2 and autism.
BACKGROUND
Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role.


METHODS
As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland.


RESULTS
Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor.


CONCLUSIONS
We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.
Weiss
Lauren A
LA
Autism Consortium , Boston, USA.
Shen
Yiping
Y
Korn
Joshua M
JM
Arking
Dan E
DE
Miller
David T
DT
Fossdal
Ragnheidur
R
Saemundsen
Evald
E
Stefansson
Hreinn
H
Ferreira
Manuel A R
MA
Green
Todd
T
Platt
Orah S
OS
Ruderfer
Douglas M
DM
Walsh
Christopher A
CA
Altshuler
David
D
Chakravarti
Aravinda
A
Tanzi
Rudolph E
RE
Stefansson
Kari
K
Santangelo
Susan L
SL
Gusella
James F
JF
Sklar
Pamela
P
Wu
Bai-Lin
BL
Daly
Mark J
MJ
D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods