Two Major Papers Point to Many New Gene Mutations Capable of Causing Autism Spectrum Disorder

Matthew State, M.D., Ph.D. - Brain & behavior research expert on autism
Matthew State, M.D., Ph.D.

Two new studies of DNA sampled from people with autism spectrum disorder (ASD)––the largest such studies ever––have provided the most vivid picture so far of autism’s genetic complexity. Together, they identify dozens of genes not previously linked with autism causation. Based on findings to date, they predict that eventually, as techniques improve and more patients are studied, hundreds of genes will be found to play a role in ASD.

The two studies appeared online October 29th, ahead of their publication in Nature. Six former recipients of NARSAD Grant awards, two members of the Foundation’s Scientific Council, and a recent winner of the Foundation’s Ruane Prize for Outstanding Achievement in Child and Adolescent Psychiatric Research were among the authors of the two papers, along with colleagues representing a total of 50 labs in the U.S. and abroad.  

An important fraction of ASD is traceable to inherited mutations, seen in affected children and also, typically, in one parent. However, both of the new studies revealed the powerful additional contribution to autism causation of so-called de novo (new) mutations. These mutations are seen in an affected child but not in either parent. In other words, de novo mutations are not inherited but rather occur when sperm and egg combine to form a unique individual. De novo errors can take a variety of forms, ranging from single-letter “spelling” mistakes in our DNA to large swaths of genome that have been deleted or added in extra copies.  One of the new papers predicts that at least 30 percent of all autism is caused by de novo mutations.

Some de novo mutations are harmless.  Others probably contribute to risk, in the presence of other factors. But a number of those identified in the new studies are what scientists call likely gene-disrupting mutations, or LGDs. When an LGD mutation (whether inherited or de novo) occurs in a gene that plays a vital role––for instance, in the wiring-up of the brain and nervous system early in development––it can have a devastating impact. Working backward from mutations of this kind, investigators in the newly published studies and others are trying to piece together how such genetic errors actually perturb human biology to generate the range of symptoms seen in people with ASD.  

In one of the studies, 107 genes were identified as “enriched” in a sample of 3,871 individuals with ASD. In the other study, 27 genes with de novo LGD mutations were analyzed. A clear pattern emerged when researchers looked at the work these genes normally perform in cells. In both studies, the affected genes are normally activated in the building and maintenance of neural networks, particularly the communication junctions between neurons called synapses. Other genes observed to be “disrupted” in the two studies included transcriptional genes, which generate proteins that regulate the activity of other genes (including those especially active during early development of the brain). Still other affected genes help regulate the way our genetic material is packed inside the nucleus of cells, in bundles called chromatin. Proteins that help reshape these bundles are essential in determining which genes can be activated at any given moment.

Both papers noted overlap in the list of ASD-linked genes conferring risk, with risk genes identified in studies of other psychiatric illnesses. In the words of the authors of one of the papers: “De novo mutations in ASD, intellectual disability, and schizophrenia cluster to synaptic genes, and synaptic defects have been reported in models of these disorders.” In this way and perhaps others, the new research supports the notion of overlap among genetic factors that cause or confer risk for a number of serious brain disorders.  

Contributing to these research studies include: Christian Marshall, Ph.D. (2007 NARSAD Young Investigator Grantee), Michael Owens, M.D., Ph.D. (two-time NARSAD Grantee), Shaun Matthew Purcell, Ph.D. (2006 NARSAD Young Investigator Grantee), Abraham Reichenberg, Ph.D. (2004 NARSAD Young Investigator Grantee), Lauren Weiss, Ph.D. (2010 NARSAD Young Investigator Grantee), Pamela Sklar, M.D., Ph.D. (Foundation Scientific Council Member and two-time NARSAD Grantee), Matthew State, M.D., Ph.D. (2012 Foundation Ruane Prizewinner for Outstanding Achievement in Child and Adolescent Psychiatric Research), Christopher Walsh, M.D., Ph.D. (two-time NARSAD Grantee), and Foundation Scientific Council Member Joseph Buxbaum, Ph.D.

Read the abstracts from both research papers: