Blood-Based Transcriptomic Biomarker Profiles of Autistic Spectrum and Other Developmental Disorders

Background: One way to combat autistic spectrum disorders (ASDs) would be to discover biological markers—or “biomarkers”—for these illnesses, which potentially could revolutionize their rational diagnosis and management.  Biomarkers could facilitate diagnosis, lead to earlier identification and intervention, and possibly suggest “treatable targets” for medicinal chemistry and drug-discovery research.  Given such immense promise, ASD biomarkers (especially genomic biomarkers, given the high heritability of ASDs) have been pursued through many decades and approaches, but little headway has been made focusing on individual biomarkers in isolation.  Objectives: For the past three years, we have been studying young children with, or at-risk for, a variety of neurodevelopmental disorders with the intent of identifying multi-modal biomarkers of presentation, course, and treatment-response of ASDs.  Here we report cross-sectional results of whole-transcriptome expression profiling in freshly drawn peripheral blood mononuclear cells (PBMCs) from Wave I of data-collection, when the enrolled infants and toddlers were first evaluated and diagnosed with (or identified as being at-risk for) an ASD, language delay (LD), other developmental delay (DD), or judged to be typically developing (TD), between the ages of 12 and 46 months.  We also evaluated subjects who initially failed the developmental screening but were later judged to be developing typically (type-I errors; TIEs).  Methods: After ensuring mRNA quality, we assayed PBMC mRNA expression profiles on Illumina WG-6 microarrays.  Data were transformed, normalized, and adjusted for probe GC content before a further assessment of quality was made.  Gene expression intensities were modeled as dependent measures in ANCOVAs with diagnosis as primary predictor and age and sex as covariates.  Shared and unique expression profiles were identified by intersection-union tests.  The biological characteristics of sets of dysregulated genes were determined by analyses of pathways, ontologies, and protein domains in DAVID.  Results: After applying all quality controls, the final sample left for the present analyses included 60 subjects with or at-risk for autistic disorder (AD), 23 subjects with or at-risk for pervasive developmental disorder not otherwise specified (PDD-NOS), 17 subjects with or at-risk for a DD, 34 subjects with or at-risk for a LD, 27 TD subjects, and 41 TIE subjects.  All groups were comparable in their male:female ratio, and most groups were comparable in mean age, except the LD and TIE groups which were significantly younger than each of the other diagnostic groups.  We found numerous genes with low false-discovery rates that distinguished developmental disorders from each other and from TD and TIE subjects.  The 313 genes that were most reliably changed in AD subjects relative to both TD and TIE subjects were most strongly associated with mitotic cell cycle regulation; other biological processes over-represented among the dysregulated genes included endopeptidase activity, cerebral cortex development, microtubule processes, negative regulation of neuron apoptosis, and neuron migration.  Conclusions: PBMCs may serve as a useful tissue for deriving biomarker profiles of ASDs that are highly specific to particular neurodevelopmental disorders.  Ongoing longitudinal analyses of these subjects will determine if these blood-based biomarker profiles fluctuate as symptom profiles change over time with intensive behavioral treatment.