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Whole-Genome Sequencing Reveals Plethora of Autism-Related Mutations

Janelle Weaver, Ph.D.

Sequencing the entire genome, rather than just the exome, reveals more information about the genetic basis of autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a highly heritable disease involving more than 100 genes, but because of heterogeneity among affected individuals, a more complete picture of the genetic causes has remained elusive. In the past, scientists have used microarrays to identify copy number variations associated with ASD and sequenced exomes or protein-coding regions of the genome to reveal genes contributing to disease risk.

Identification of ASD-related genetic variants by whole-genome sequencing. Source: Am J Hum Genet.

Now, a study published July 11th in the American Journal of Human Genetics has shown that sequencing genomes in their entirety can reveal even more information on ASD-related mutations than whole-exome sequencing because of more uniform coverage. By providing more information about an individual’s particular set of mutations, whole-genome sequencing could also help clinicians develop personalized treatment strategies.

“The detection rate of mutations that we consider to be clinically relevant is better than whole-exome sequencing studies, even based on our small sample size of 32 families,” says study author Yong-hui Jiang, who treats individuals with ASD and conducts research on the genetic basis of neurodevelopmental disorders at Duke University School of Medicine. “This approach is promising and may have a direct impact on patient diagnosis and evaluation in the future.”

In the new study, Jiang and his collaborators used whole-genome sequencing to detect de novo and rare inherited genetic variants in 32 families affected by ASD. Using this sequencing approach in combination with bioinformatic analyses, the researchers identified potentially significant variants in half of the families examined—the highest proportion ever reported, according to the study authors. Moreover, 11% of the de novo and clinically relevant mutations identified in the study would probably not have been captured by exome sequencing.

The genes implicated in Jiang’s study had previously been linked to ASD or related condition, such as intellectual disability and seizures. In six of the families, individuals with ASD had deleterious de novo mutations, such as loss-of-function or damaging missense mutations. In addition, ten families were affected by X-linked or autosomal inherited alterations. Moving forward, the researchers plan to expand the study beyond 32 families and conduct experiments to examine the function of the variants identified.

Still, it might some time before whole-genome sequencing studies of this kind become the standard, given the exorbitant cost of whole-genome sequencing and the challenges associated with data storage and bioinformatic analyses. “The computational power required to analyze the whole-genome sequencing data is significantly larger than for whole-exome data,” says Jiang. “We used a supercomputer and a large bioinformatic team to handle this data. For an individual investigator or lab, it’s probably not very practical if there is a large sample size.”

Jiang himself will probably continue to use whole-exome sequencing in the clinic, but he predicts that researchers will eventually switch to whole-genome sequencing. “The question of whether whole-genome sequencing will become more feasible is a financial issue,” says Jiang. “Technically, I think that whole-genome sequencing is certainly better than whole-exome sequencing. Our very small-scale study shows that whole-genome sequencing is probably the way to go for the long term. But in practical terms, whole-exome sequencing will probably dominate in clinical practice because it’s a lot cheaper and the data analysis is much easier.”

Michael Ronemus, an expert in the genetic basis of ASD at Cold Spring Harbor Laboratory, agrees. “There’s no doubt the field will switch over to whole-genome sequencing for the purpose of discovery. It’s just a matter of time,” says Ronemus, who was not involved in the new study. “But I don’t think clinicians will switch over to whole-genome sequencing anytime in the near future. Our expectation is that sooner or later we will find all of the hundreds of genes that can cause autism, so there won’t be a lot of reason to look elsewhere in the genome at a much greater cost.”

Jiang YH, Yuen RK, Jin X, Wang M, Chen N, Wu X, Ju J, Mei J, Shi Y, He M, Wang G, Liang J, Wang Z, Cao D, Carter MT, Chrysler C, Drmic IE, Howe JL, Lau L, Marshall CR, Merico D, Nalpathamkalam T, Thiruvahindrapuram B, Thompson A, Uddin M, Walker S, Luo J, Anagnostou E, Zwaigenbaum L, Ring RH, Wang J, Lajonchere C, Wang J, Shih A, Szatmari P, Yang H, Dawson G, Li Y, Scherer SW. 2013. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet. doi: 10.1016/j.ajhg.2013.06.012.

Keywords:  genomics autism