Open Access Research

Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population

Nori Matsunami1, Charles H Hensel2*, Lisa Baird1, Jeff Stevens1, Brith Otterud1, Tami Leppert1, Tena Varvil1, Dexter Hadley3, Joseph T Glessner3, Renata Pellegrino3, Cecilia Kim3, Kelly Thomas3, Fengxiang Wang3, Frederick G Otieno3, Karen Ho2, Gerald B Christensen4, Dongying Li5, Rytis Prekeris5, Christophe G Lambert4, Hakon Hakonarson36 and Mark F Leppert1

Author Affiliations

1 Department of Human Genetics, University of Utah, Salt Lake City, UT, USA

2 Lineagen, Inc, Salt Lake City, UT, USA

3 Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

4 Golden Helix, Inc, Bozeman, MT, USA

5 Department of Cell and Developmental Biology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

6 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

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Molecular Autism 2014, 5:5  doi:10.1186/2040-2392-5-5

Published: 27 January 2014



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.


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.


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.


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.

Familial autism; Haplotype sharing; DNA sequence variants; Case/control study