Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
Bucan
Maja
M
Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, California, United States of America.
Abrahams
Brett S
BS
Wang
Kai
K
Glessner
Joseph T
JT
Herman
Edward I
EI
Sonnenblick
Lisa I
LI
Alvarez Retuerto
Ana I
AI
Imielinski
Marcin
M
Hadley
Dexter
D
Bradfield
Jonathan P
JP
Kim
Cecilia
C
Gidaya
Nicole B
NB
Lindquist
Ingrid
I
Hutman
Ted
T
Sigman
Marian
M
Kustanovich
Vlad
V
Lajonchere
Clara M
CM
Singleton
Andrew
A
Kim
Junhyong
J
Wassink
Thomas H
TH
McMahon
William M
WM
Owley
Thomas
T
Sweeney
John A
JA
Coon
Hilary
H
Nurnberger
John I
JI
Li
Mingyao
M
Cantor
Rita M
RM
Minshew
Nancy J
NJ
Sutcliffe
James S
JS
Cook
Edwin H
EH
Dawson
Geraldine
G
Buxbaum
Joseph D
JD
Grant
Struan F A
SF
Schellenberg
Gerard D
GD
Geschwind
Daniel H
DH
Hakonarson
Hakon
H
D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics*; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005091:Exons; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D019006:Neural Cell Adhesion Molecules; D010375:Pedigree; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult
D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases