Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population.
BACKGROUND
Genetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken.


METHODS
We identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population.


RESULTS
We identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci.


CONCLUSIONS
Our study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants.
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Nori
N
Matsunami
Lineagen, Inc, Salt Lake City, UT, USA.
Charles H
CH
Hensel
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Lisa
L
Baird
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Jeff
J
Stevens
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Brith
B
Otterud
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Tami
T
Leppert
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Tena
T
Varvil
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Dexter
D
Hadley
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Joseph T
JT
Glessner
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Renata
R
Pellegrino
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Cecilia
C
Kim
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kelly
K
Thomas
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Fengxiang
F
Wang
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Frederick G
FG
Otieno
Lineagen, Inc, Salt Lake City, UT, USA.
Karen
K
Ho
Golden Helix, Inc, Bozeman, MT, USA.
Gerald B
GB
Christensen
Department of Cell and Developmental Biology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Dongying
D
Li
Department of Cell and Developmental Biology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Rytis
R
Prekeris
Golden Helix, Inc, Bozeman, MT, USA.
Christophe G
CG
Lambert
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Hakon
H
Hakonarson
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Mark F
MF
Leppert