Genetic Research Leading to Advances in Autism Care

Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with a wide range of severity and symptoms affecting 1 out of 68 children in the United States. While there is currently no medicine for this complex condition, discovering genetic causes of ASD will help accurate diagnosis and prediction of additional likely symptoms, thereby improving medical treatment. Genetic findings can also provide families with critical information about the clinical course of the disease and provide opportunities for family counseling. New genetic findings allow scientists to conduct more specific research into the mechanisms that cause ASD as well as the many subtypes and symptoms of the condition. Finally, genetic findings also allow for detailed study of the way these genes function, which can help scientists design new treatments and develop more tailored medical support in the form of personalized medicine.

The Origins of Genetic Research in Autism

For more than 30 years, studies of families and twins have suggested that genetic factors are largely responsible for autism. For example, in identical twins who share the same genetic material, if one child has ASD the other twin also has ASD in 7-9 out of 10 cases. However in fraternal twins the concordance drops to 1 out of 10 cases.

This predisposition has its roots in mutations in our DNA, the genetic material that contains the instructions for human development and function. The DNA is organized in chromosomes, which contain molecular units called genes. Each gene contains exons, which are instructions for creating proteins.

Identifying genes underlying a disorder has many important ramifications, but of particular significance is the fact that as gene mutations are identified, the same mutation can be studied in cells in culture (in a petri dish) and in laboratory animals, such as mice. This provides a window into the molecular and cellular changes caused by the mutation, and can lead to a deep understanding of the neurobiology of the condition being studied. This understanding of the neurobiology can in turn lead to potential novel treatments.

In ASD, this approach is likely to be the cornerstone of personalized, or individualized, medicine, where treatments are tailored to the specific causes of the ASD. Examples of clinical trials based on this approach include ongoing trials in Fragile X syndrome, Rett syndrome, and Phelan-McDermid syndrome, all three of which are associated with a very high risk for ASD.

Research Hurdles

Despite the evidence supporting the major contribution of genetic factors to ASD, less than 20 percent of ASD cases are currently identified with a specific known molecular genetic cause. Numerous genetic mutations have been discovered in individuals with autism, including large abnormalities in whole chromosomes, deletions or duplications in sections of DNA, and even changes of single nucleotides within a gene. Genetic screening in children with ASD often identifies mutations in genes involved in other genetic disorders that share risk with ASD. In these cases, the genetic testing defines the diagnosis and provides tools for interpreting the complex combination of symptoms (e.g. intellectual disability, seizures), and helps families and medical professionals plan an appropriate course of action. For example, Fragile X syndrome is the most common form of inherited intellectual disability and accounts for about 2 percent of ASD cases.

In the over 80 percent of ASD cases with an identifiable cause, the uncertainty about the causes increases the emotional burden for families and poses limitations to the comprehension of the biology and the ability of scientists to develop targeted therapies.

Current Status of Genetic Research

Ongoing genetic studies are revealing the complexity and diversity of the genetic landscape of ASD: About 100 genes and 50 chromosomal abnormalities have been discovered so far, but 500-1,000 genes are estimated to contribute to risk. Increasingly sophisticated genomic technologies that analyze all genes in the genome, using a method called whole-exome sequencing (WES), are helping scientists discover new genes that contribute to risk for ASD. Scientists use these tools to uncover genetic differences in the DNA of individuals with ASD and individuals without ASD called genetic variation. Researchers are creating large groups and programs to coordinate these efforts, share data, and accelerate discoveries. One example is the Autism Sequencing Consortium (ASC) which was founded in 2010 and is led by Dr. Joseph Buxbaum. The ASC is a collaboration of over 20 international research groups with the immediate goal of analyzing exomes from 20,000 participants, with the ultimate intent of identifying genetic factors in a larger proportion of individuals with ASD.

In the last two years, several WES studies of autism have uncovered genetic variation in about 18 percent of patients with ASD. To enhance the rate of gene discovery, many studies use “trios” (examining the child with autism and his or her biological parents); comparing the child’s DNA with the parents’ DNA allows for the identification of new (“de novo”) mutations. These are DNA changes that neither parent possesses but that occurred in the sperm or eggs of the parents. This has the advantage of pinpointing potentially harmful mutations among the abundant genetic variation present in all genomes, even those of healthy individuals. Studies with the trio design performed on 1,000 families have revealed that about 6 percent of patients carry rare, de novo single-nucleotide mutations that disrupt the function of a specific gene, thereby causing the loss of the function played by the protein encoded by the gene. Complementary studies have shown that in 5 percent of ASD cases the disruptive mutations are inherited from both parents or from the mother in affected boys with mutations in genes located on the sex chromosome X. Another 7 percent of affected individuals carry a small CNV (microscopic deletion or duplication of DNA segments involving one or more genes), occurring as de novo or transmitted from the parents.

So, just in the past two years, scientists have shown that the technique of WES alone can make a genetic finding in 18 percent of individuals with autism. Two very large WES studies seeking to identify many dozens of ASD genes are currently being completed and will likely be published in 2014.


Joseph D. Buxbaum, PhD, is a world-recognized molecular geneticist and director of Mount Sinai’s Seaver Autism Center for Research and Treatment, which is conducting several clinical trials based on gene discovery in ASD. Silvia De Rubeis, PhD, is a Seaver Postdoctoral Fellow in the Seaver Autism Center for Research and Treatment.

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