This article was originally written for Genetic Alliance.
Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with a wide range of severity and symptoms. ASD affects 1 in every 88 children in USA and manifests with an array (‘spectrum’) of disabilities. An individual is diagnosed with ASD when s/he is shown to have persistent deficits in (I) social communication and social interaction, and (II) restricted patterns of behavior, interests, or activities [Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V)]. Difficulty with social communication in ASD can manifest even at an early age, with symptoms such as poor eye contact, limited facial and body language, and difficulty understanding nonverbal communication such as facial expressions. Individuals with ASD often have particular difficulty with social interactions. They may have difficulty engaging and maintaining social contacts, connecting with and sharing interests and emotions with their peers, and adjusting their behavior according to social context. Individuals with ASD can also experience repetitive behaviors (‘stereotypies’), including repetition of movements (e.g., hand flapping), actions (e.g., flipping objects), or speech (e.g. repeated words or phrases). Children and adults with ASD may also have exceedingly narrowed interests such as fascination for or persistent preoccupation with unusual objects and inflexibility to routines in their daily activities, which can take the form of rituals, insistence of consistency, and distress at small changes. Unusual sensory responses, including, for example, sensitivity to pain/temperature, fixation with lights, or aversion to specific sounds, have also been documented. Individuals with ASD may or may not have language impairments, which often occur in combination with other conditions, such as intellectual disability and seizures. The severity of symptoms can vary significantly: some children are mildly affected, while others are more severely impacted. There is still no medicine for ASD, but appropriate behavioral interventions have strong beneficial effects.
ASD is a complex condition, and many factors contribute to risk. For over 30 years, studies of families and twins have suggested that genetic factors are largely responsible for autism. In identical (monozygotic) 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, while in fraternal (dizygotic) 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 how we function. The DNA is structurally organized in chromosomes, which contain molecular units (genes), each composed of a sequence of nucleotides. Each gene contains exons, which are instructions for creating proteins (each protein carries out specific functions in the cell, thus translating the genetics information of the gene). Although the collection of all exons (exome) contains a substantial portion of meaningful DNA, it only represents 2% of the entire genetic repertoire (genome).
Identifying genes underlying a disorder has many important ramifications, discussed briefly below. But one that should be appreciated is that, as gene mutation are identified, the same mutation can be studied in cells in culture (in a petri dish) and in laboratory animals (most often 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 of rational medicine 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 these syndromes are associated with a very high risk for ASD.
Despite the evidence supporting the major contribution of genetic factors to ASD, less than 20% of ASD cases are currently identified with a specific known molecular genetic cause. Numerous genetic mutations have been discovered in individuals with autism. These range from large abnormalities in whole chromosomes to deletions or duplications in sections of DNA, all the way down to 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% of ASD cases.
In the over 80% 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.
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 500-1000 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, a collaboration of over 20 international research groups founded in 2010 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% of patients suffering from 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 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% 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% 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% of affected individuals carry a small CNV (microscopic deletion or duplication of DNA segments involving one or more genes), occurred as de novo or transmitted from the parents. So, just in the past 2 years, scientists have shown that the technique of WES alone can make a genetic finding in 18% of individuals with autism. Two very large WES studies, in 8-10,000 samples, are being completed and will likely be published this year. These studies will identify many dozens of ASD genes.
Discovering genetic causes of ASD will help accurate diagnosis and prediction of additional likely symptoms, providing better medical treatment. Genetic findings can also provide families with critical information about the clinical course of the disease and can 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. As noted above, several important clinical trials are being carried out based on gene discovery in ASD, including several at the Seaver Autism Center. You can find out more about the Seaver Autism Center at www.seaverautismcenter.org.
About the Authors
Silvia De Rubeis, PhD and Joseph D Buxbaum, PhD are from the Seaver Autism Center for Research and Treatment of the Icahn School of Medicine at Mount Sinai in New York. Dr. Buxbaum is co-editor of The Neuroscience of Autism Spectrum Disorders, a book that offers a survey and synthesis of the most important findings of the neuroscience behind autism of the past 20 years.