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Gene Deletions May Be Implicated in Autism


By Aaron Krol 

October 3, 2013 | Studying the genetic causes of autism has been a longstanding challenge for researchers. Autism’s complex causality is still little understood, but it is widely agreed to involve an interconnected and changeable network of genetic and environmental factors, making it difficult to pin down specific genetic variants that contribute to the condition. Hundreds of single-nucleotide polymorphisms (SNPs) have been flagged for their potential involvement in autism spectrum disorders (ASDs), and it is still not clear which are the most promising avenues for future study. Furthermore, while ASDs are heritable, strong selection pressures ensure that the genetic factors in a majority of cases will be rare de novo mutations. With any given SNP unlikely to be implicated in a given case of autism, genomic data from tens of thousands of ASD individuals are needed to draw firm conclusions. Most autism studies to use genome sequencing so far have focused on these de novo single-nucleotide mutations, in the hopes of discovering telling patterns among them.

New Genetic Targets 

Now a team led by Dr. Joseph Buxbaum, the director of the Seaver Autism Center at Mt. Sinai, has released the results of a large genomic study looking for a different source of genetic variability that may contribute to autism. Rather than examining SNPs, Buxbaum’s team considered the number of gene deletions in a cohort of ASD individuals and a matched control group. All subjects received whole exome sequencing, and their exomes were analyzed using the recently-developed eXome Hidden Markov Model (XHMM) program, which is able to sensitively identify small copy number variations like gene deletions.

Like SNPs, gene deletions can be either inherited or de novo events – but they are far less common, with a typical individual having between one and two among their roughly 22,000 genes. In the cohort of 379 controls, XHMM found 583 deletions, consistent with that average. Among the 431 members of the ASD group, however, XHMM found a combined 803 deletions – a significant difference. ASD individuals were also more likely to have multiple gene deletions.

Because cost-effective whole exome sequencing, and analytical tools like XHMM that can detect copy number variations in large sets of data, are both relatively new phenomena, Dr. Buxbaum’s was the first study to look for gene deletions in ASD individuals, with funding from the Seaver Foundation and the National Institute of Mental Health. The results not only implicate gene deletions in the development of ASDs, but also provide new guidance into which genes may have particular significance for autism. Already the researchers at Seaver have noticed that many of the gene deletions in their ASD group occurred in genes connected with autophagy, the process by which cellular components are broken down. Autophagy may play a key role in how synaptic connections develop in the brain.

A Small Piece of a Big Picture 

Still, the team regards their work less as a new direction for autism research, and more as supportive of existing genetic studies. As an extension of his work at Seaver, Dr. Buxbaum is also co-director of the Autism Sequencing Consortium (ASC), a body of over 25 research groups who are seeking to collectivize their genetic data on ASD individuals. While many projects have taken whole exome sequences of ASD individuals, the information gathered has historically been scattered across multiple databases. The ASC, supported by the NIH, the Simons Foundation, and advocacy group Autism Speaks, wants to funnel all that data into a single repository at Mt. Sinai, with a goal of collecting 30,000 whole exomes for more detailed analysis. The recent gene deletion study fits comfortably in that framework.

The study has been published in the American Journal of Human Genetics.

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