Yesterday, Autism Awareness Month in the US drew to a close. To mark this, Dr Joseph Buxbaum and Dr Silvia De Rubeis of the Seaver Autism Center for Research and Treatment tell us about the condition and the exploration of the genetics behind it.
Autism spectrum disorder (often simply known as autism) describes a group of neurodevelopmental disorders that manifest with an array of disabilities. A person is diagnosed with autism when they have persistent deficits in social communication and social interaction, and restricted patterns of behavior, interests, or activities.
A recent report released from the Centers for Disease Control and Prevention (CDC) indicates that 1 in 68 children in the US suffer from autism, while boys are nearly five times more likely to be diagnosed than girls (1 in 42 males, 1 in 189 females). These figures are dramatically increasing: the prevalence is 30% higher than that reported in 2012 (1 in 88 children).
Is this reflecting a true hike in autism incidence? Although we can’t exclude modest changes in risk, epidemiological studies suggest that this increase is likely to be inflated by increased awareness and medical surveillance, and improved diagnosis using standardized criteria.
The genetics of autism
Autism is a complex condition, and many factors contribute to susceptibility. Studies of families and twins indicate a strong genetic component: in identical twins, who share the same DNA, if one child has autism the other twin also has it in 7-9 out of 10 cases, while in non-identical twins this drops to 1 out of 10 cases. This predisposition has its roots in mutations that can compromise the function of our genes.
Until recently, less than 20% of autism cases could be identified as having a genetic cause. In the remaining 80%, the uncertainty about the causes increases the emotional burden for families and creates challenges in developing targeted therapies. There is still no medicine for autism: genetic studies are the first step towards the understanding of its neurobiology and the development of novel therapeutics, especially in the form of personalized medicine.
Ongoing genetic studies are revealing the complexity of the genetic landscape of the condition: about 100 genes and 50 chromosomal abnormalities have been discovered so far (reviewed here), but 500-1000 genes are estimated to contribute to risk.
Advancing knowledge and accelerating findings with new technology
In the last two years, studies using increasingly sophisticated genomic technologies, such as whole-exome sequencing, have made tremendous progress in the discovery of new risk genes. Many of these studies have focused on trios (the child with autism and their biological parents): comparing the child’s DNA with the parents’ DNA allows the identification of new (de novo) mutations. Just in the past 2 years, whole-exome sequencing conducted on about 1,000 trios have identified a genetic cause in 18% of individuals with autism.
To accelerate findings, researchers are creating large consortia. One example is the Autism Sequencing Consortium (ASC), a collaboration of over 20 international research groups, including ours, and which was founded by one of us in 2010 (Dr. Joseph Buxbaum). The consortium’s goal is to study 20,000 participants. We’re now completing the analysis of more than 14,000 samples, and our data are identifying many dozens of ASD genes, and unveiling pathways underlying autism.
Genetic studies have numerous repercussions. Genetic findings are essential for accurate diagnoses, and predictions of additional symptoms. Also, genetic data can be reproduced in laboratory models (e.g. cells or organisms), providing tools to study the mechanisms of the disease, and design new drugs that will lead to more tailored medical treatments.
In fact, findings in animal models have been translated into clinical trials for monogenic forms of autism. For example, the discovery that Insulin-like Growth Factor-1 (IGF-1) has beneficial effects on a mouse model for Phelan-McDermid Syndrome has promoted a clinical trial at the Seaver Autism Center for Research and Treatment.
This and other ongoing trials highlight how genetics findings applied to animal models can be translated into novel therapeutic strategies.
The great progress achieved with genomics research in the last few years brings hope to people with autism and their families: a large fraction of genetic factors underpinning autism spectrum disorder will be identified in the next years. This will lead to timely and accurate diagnosis, more targeted genetic counseling for families and improved support and care for patients.
Mapping the newly discovered genes to biological pathways will also help develop novel trials that leverage existing drugs (e.g. IGF-1 for Phelan-McDermid) or explore novel compounds. Finally, the genetics advances will represent the first step of pioneering personalized clinical care by integrating personal genomics data with ad hoc therapeutics.