Approximately 11 out of every 1,000 US children are diagnosed with Autism Spectrum Disorders (ASD) annually, according to the CDC. While autism is usually diagnosed clinically, genetic evaluations have been thought to have potential in aiding definitive and early diagnosis of autism. Such early diagnosis is essential because pharmacologic and non-pharmacologic interventions made when children are younger have been shown to lead to positive effects on habilitative progress, functional outcome, and quality of life. Since imaging may be costly and ineffective, and a brain biopsy is infeasible, developing a sensitive blood-based genetic test has been an example of a major effort on this front.
Recently, a team of researchers at Boston Children’s Hospital, led by Sek Won Kong MD, conducted the largest blood transcriptome study to date to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The team developed a prototype blood test for autism that was able to predict whether a boy was at risk for autism with up to 70 percent accuracy — a marked improvement upon other blood tests. The results of the study were published in PLoS One this past month. According to the abstract, the differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. Boston Children’s Hospital has licensed the gene signature approach exclusively to SynapDx (Southborough, Mass.).
According to Dr. Isaac Kohane, director of the Boston Children’s Hospital Informatics Program (CHIP) and senior investigator on the study:
It’s clear that no single mutation or even a single pathway is responsible for all cases,” says Kohane. “By looking at this 55-gene signature, which can capture disruptions in multiple pathways at once, we can say with about 70 percent accuracy, ‘this child does not have autism,’ or ‘this child could be at risk,’ putting him at the head of the queue for early intervention and evaluation. And we can do it relatively inexpensively and quickly.
We had a chance to speak with Dr. Kong about the test and the future of autism diagnosis:
Ravi Parikh, MedGadget: First off, give us a bit of your background. What motivated you to study autism?
Dr. Sek Won Kong: I am a psychiatrist by training, and started my research carrier in brain imaging. Brain imaging is a sort of measurable phenotype on which underlying genetic components may influence. Many psychiatric disorders have strong genetic components, but the tools were limited. When the first draft human genome was announced, I thought that unbiased, genome-wide approach to underlying genetics might be the best way to investigate complex brain disorders with high heritability. Autism is one of the most common neurodevelopmental disorders, but the pathophysiology is not known yet. A strong genetic component must be associated, however, 10-20% cases can be linked to reported genomic variants. It is important to identify cases as early as possible for early intervention, which can change the quality of life. Now tools are available, and we started using unbiased genome-wide approach to study autism.
MedGadget: Tell us about the state of blood tests for autism prior to your study. What signatures are those blood tests based on, and what were they lacking?
Dr. Kong: Cytogenetic tests for chromosomal anomalies are the only available test for screening genetic factors today. These have very low sensitivity due to only a small proportion (less than 10%) of patients having a chromosomal aberration. No other blood tests are available now. Previous works were limited by small number of samples, and by profiling lymphoblastic cell lines from the patients. We found that gene expression profiles using blood and lymphoblastic cell lines (LCL) were pretty different, and decided to characterize blood gene expression signature that reflects physiological status better over transformed cell lines. For instance, if we just focus on gene expression changes due to large structural DNA changes such as deletion and amplification, LCL can be used too. However, we wanted to know what cells were actively transcribing given DNA sequences, which is more physiological and holistic view. What you can do –engraved in DNA – is different from what you are actually doing – producing RNAs and proteins.
MedGadget: What was the accuracy of diagnosis found in your trial?
Dr. Kong: The prediction accuracy for males with autism-spectrum disorders (ASD) was 72%.
MedGadget: Clinically, what could then be the benefit of early diagnosis of autism? Is treatment or management keeping pace with changes in diagnosis?
Dr. Kong: Early intervention and individualized special education are important to change the course of disorder and to improve the quality of life as an independent social being. There seems to be a window when brain has more plasticity. New fascinating results of early intervention on brain function are coming out.
MedGadget: What is the stage of the blood test now in terms of marketing development and clinical availability? Additionally, could you tell us more about the licensure of the gene signature approach to SynapDx?
Dr. Kong: A larger scale replication of the result is critical to develop our finding into a clinically available test. Few studies are underway, and we will see the results in next a couple of years. The company (SynapDx) licensed our approach a couple of years ago. They are actively pursuing this as a diagnostic test, so definitely facilitate the whole process to clinic.
MedGadget: What does this novel blood test tells us about the biochemical mechanism of autism spectrum disorders? Do you believe it adds to or refutes existing conceptions of mechanisms of autism?
Dr. Kong: We cannot speculate any mechanism from our result. Autism is the disorder of developing brain. However, different tissues share a large number of active genes and proteins as all cells in our body operate with a limited number of genes and proteins. As shown in our paper, two pathway clusters seem to be interesting, which are immune response and synaptic plasticity pathways. One of the key findings was that only a proportion of cases presented significance for immune, synaptic, or immune and synaptic.
We were extremely excited to learn more about blood-based diagnostics for autism and are looking forward to their future in clinical practice!
Check out the original article published in PLoS One: Characteristics and Predictive Value of Blood Transcriptome Signature in Males with Autism Spectrum Disorders
Press release: A better early blood test for autism
