Association and mutation analyses of 16p11.2 autism candidate genes.
BACKGROUND
Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a approximately 500-700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown.


RESULTS
To identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings.


CONCLUSIONS
We have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.
Kumar
Ravinesh A
RA
Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.
Marshall
Christian R
CR
Badner
Judith A
JA
Babatz
Timothy D
TD
Mukamel
Zohar
Z
Aldinger
Kimberly A
KA
Sudi
Jyotsna
J
Brune
Camille W
CW
Goh
Gerald
G
Karamohamed
Samer
S
Sutcliffe
James S
JS
Cook
Edwin H
EH
Geschwind
Daniel H
DH
Dobyns
William B
WB
Scherer
Stephen W
SW
Christian
Susan L
SL
D000818:Animals; D001321:Autistic Disorder / Q000209:etiology / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian; D005091:Exons / Q000235:genetics; D005192:Family Health; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics
D008565:Membrane Proteins; C513545:SEZ6L2 protein, human