Researchers from the UC San Diego, University of Cambridge, University of Cyprus and the Scripps Institute report finding a highly accurate blood-based measure that could lead to development of a clinical test for autism spectrum disorder (ASD) risk in males as young as one to two years old. The test could be done in community pediatric settings. The team state that the degree of accuracy out-performs other behavioural and genetic screens for infants and toddlers with ASD described in previous studies.
The causes of ASD are complex and diverse, making it difficult to conclusively diagnose the disease much before a child’s fourth year of life. Indeed, the median age of diagnosis in the United States is 53 months.
Now, in the proof-of-principle study the team have identified blood-based genomic biomarkers that differentiated toddlers with ASD, ranging in age from one to four years old, from a control group of toddlers without ASD. Blood samples were taken at the child’s initial clinical intake. Importantly, the control group consisted of a mix of young boys commonly seen in community clinics, with typical development, mild language delay, transient language delay and global developmental delay. Against this control group, the researchers identified a genetic signature that identified 83 percent of ASD toddlers.
The study used an unbiased systems biology-based method to search for genes and gene pathways in blood samples that best distinguished ASD infants and toddlers from typically developing toddlers and toddlers with non-autism developmental delays. Specifically, the researchers measured leukocyte (white blood cell) RNA expression levels.
The researchers explain that ideally, biomarkers come from tissue affected, but in ASD this is the brain, which is obviously an inaccessible tissue. Peripheral blood of living ASD infants and toddlers is an important alternative, and obtaining blood samples is routine and safe and, thus, is a preferable and accessible tissue for identifying signatures of ASD that could be used in clinical screening and follow-up evaluations.
It has always been theorised that human blood would carry autism-relevant molecular signatures that can be used to detect the disorder at very young ages. It might also reflect aspects of the disrupted biology underlying neural defects.
In fact, the researchers found gene expression differences between ASD and non-ASD in genes related to translation and immune/inflammation functions, as well as cell adhesion and cell cycle. These ASD signature classifier genes are among those that effect early brain development.
The team state that new studies point to autism beginning in the womb and published one such widely reported study last year detailing disrupted brain development in post-mortem brains of autistic children. The current study shows examination of the gene expression profiles at the very early age of initial clinical detection reveals both strong evidence of early biological processes in ASD and abnormal signals with the potential to serve as an early, practical biomarker of risk for the disorder in general pediatric settings.
Two different analyses of blood were conducted with samples involving two cohorts of study participants. 147 toddlers (91 with ASD, 56 control) in the first group and 73 toddlers (44 ASD, 29 control) in the second group. The first assay identified an ASD genomic signature 83 percent of the time; the second had a 75 percent accuracy rate.
Young male toddlers with autism were the focus of the study because autism is four times more prevalent in males than in females. This meant the team were able to more quickly recruit and test samples of autism males.
The team also theorise that the genetics and molecular bases of autism may differ somewhat in affected males and females. Therefore, different signatures might need to be discovered and developed in each gender in ASD with current work aimed at recruiting sufficiently large samples of females to begin work to discover possible gene expression markers for them.
The team stress that this is a first step toward a possible means of diagnosing autism much earlier than current methodologies, one that would greatly boost the efficacy of intervention and remedial treatments. Though proof-of-principle the researchers state that the findings are encouraging.
The team summise that the study showed that a blood-based clinical test for at-risk male infants and toddlers could be refined and routinely implemented in pediatric diagnostic settings.