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A New Genetic Perspective on Autism Spectrum Disorders

Recent genetic studies in autism spectrum disorders (ASDs) support an important role for what are being termed multiple “rare variants” in these conditions. ”Rare variants” include what we think of as mutations, and can be the cause of an ASD when they are found. This is an extremely significant finding because the identification of causal variants may lead to earlier diagnosis, genetic counseling, the conceptualization of new approaches to therapeutics, and the development of model systems in which new therapeutics can be tested. There is therefore plenty of cause for optimism in the field.

The most dramatic example of this new approach is the recently initiated large-scale clinical trial in Fragile X Syndrome (FXS). FXS accounts for approximately 2% of ASD cases and FXS screening is already standard in most cases with an ASD. When a clinician identifies the FXS mutation in a child affected with an ASD, the clinician will conclude that the FXS is the cause of the ASD. This, in turn, leads to opportunities for genetic counseling and also to earlier behavior intervention, which is associated with better long-term outcomes. What is perhaps less appreciated is that with such a causal genetic disorder, it is now possible to genetically modify laboratory animals to re-create the genetic alteration for further study. Detailed analysis of a genetically modified mouse that modeled FXS gave rise to a hypothesis that over-expression of specific proteins in the brain produced the cognitive deficits in FXS. As a result of this hypothesis, drugs that targeted this pathway were tested in these genetically modified mice and were shown to correct some of the cellular and behavioral deficits observed in the mice. As a result of this, beginning in January 2008, there is now a large-scale clinical trial in FXS with a drug targeting this pathway. While the results are not yet in, there is great optimism that this general approach will produce new therapeutic approaches to the ASDs.

By way of background, it is important to note that twin and family studies in ASD have indicated that the ASDs are the most heritable (i.e., genetic) of psychiatric conditions. This could be quantified with an estimate of heritability of over 90%. For many years it was thought that this genetic liability to ASDs was primarily caused by the interaction of several common genetic variations in an individual. In this model, a common genetic variant by itself was not deleterious and could even have a positive effect on one who carried it, but when too many were present in the same individual, the total effect was negative. Imagine, for example, if one genetic variant made a person more organized or focused but several more genetic variants with the same effect, acting additively, would result in excessive organization or a focus that was too narrow. This has been called the common variant model.

In contrast, in the multiple rare variant model, a large number of rare, and even very rare, genetic variants underlie a disorder, typically with just a single rare variant found in each individual. Unlike the common variants, where each one has only very modest effects, these rare variants can have quite substantial effects and may contribute the major part of the risk for a given individual. The rare variants that we are all most familiar with are the rare deleterious mutations found in many disorders, such as that found in FXS. There have been theoretical arguments in favor of rare variants in ASDs, and recent studies have provided empirical evidence for this model.

Even before the advances of the last two years, it was already known that a variety of genetic conditions can present with ASDs. These include FXS, but also Angelman syndrome (AS), Prader-Willi syndrome (PWS), and the chromosome 15q11-13 duplications. More recently, rapid advances in genetic technology have allowed for researchers and clinicians to scan the chromosomes to identify new genetic conditions caused by small (submicroscopic) chromosomal deletions and duplications (often called copy number variants or CNVs) and to rapidly scan individual genes for mutations. Some of the recent CNVs that have been identified in ASDs include the chromosome 16p11 deletions, chromosome 22q13 deletions, CNTN gene deletions, and NRXN1 gene deletions. Some of the recently identified gene mutations identified in ASDs include mutations in the SHANK3, NLGN3, NLGN4, and PTEN genes. In each of these cases, the CNV or mutation is the major cause of the ASD in that instance. Every time such a cause is identified, the family can be counseled as to recurrence risk (the chance that another family member will have an ASD), and the disorder can be identified earlier in its course (allowing for earlier intervention). Moreover, genetically modified mice can be developed to study the development and prevention of the disorder. As a concrete example, our laboratory has mice that capture several of these genetic conditions that lead to ASDs, including the 22q13 deletion and the SHANK3 mutation, and we are studying the changes in the mouse brain resultant from these mutations. We are already considering ways to manipulate these animals to reverse the mutation-induced changes.

As we as a field find more and more of these rare variants, one can ask how well we can identify the genetic cause of ASD in a particular case. With modern methods, the better sites are successful in as many as 20-30% of the cases and there is every reason to expect that this rate will double in the next 2-3 years.

In summary, the developments of the past 2 years — where we have done better and better in identifying genetic changes leading to ASDs — give plenty of reasons for optimism as we all search for the means of better treating ASDs. As there is empirical evidence that ASDs can respond to intensive behavioral intervention, identifying individuals with greater risks of ASD at an earlier age will have important clinical and practical implications. As rare variants in ASD continue to be identified, animal models that recapitulate the genetic change(s) can be developed. These models can clarify the progression of ASDs, and will be useful to evaluate novel pharmaceutical interventions. An exciting development that serves as a model going forward is the new understanding of the basis of FXS, which has led to the initiation of a recent large-scale clinical trial in FXS. As additional rare variants associated with ASDs are identified, novel therapeutic approaches will be developed, some of which may be specific to a given rare variant (“individualized medicine”) and some of which may prove effective across ASDs with differing etiologies.

Research forms the cornerstone of these approaches and I encourage all families to learn about current research and consider joining in this important endeavor. The Seaver Autism Center for Research and Treatment has received support from the Seaver Foundation, the Handler Foundation, the National Institutes of Health, Autism Speaks, the Simons Foundation, and many individual donors. The Seaver Autism Center is a site where families can access exceptional clinical care in ASDs, including comprehensive behavioral and genetic evaluations and state of the art treatment. Individuals with ASDs and their families will also find the Seaver Autism Center a welcoming place where they can learn more about ASDs and participate in research dedicated to discovering the cause(s) of ASD and developing new medical and behavioral treatments. For more information, please call 212-241-0961.

Dr. Joseph D. Buxbaum, PhD, is Director at the Seaver Autism Center for Research and Treatment, Chief of the Division of Basic Neuroscience in Psychiatry, Head of the Laboratory of Molecular Neuropsychiatry, and Professor at the Departments of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at Mount Sinai School of Medicine in New York.

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