Autism spectrum disorder pathway

ASD is a multi-factorial disorder thought to have genetic and environmental inputs. Genetic causes, including gene defects and chromosomal anomalies, have been found in 10%–20% of individuals with ASD². The etiology of ASD is confirmed to be multigenic and highly heterogeneous, with very few of the same genetic variants present in a significant percentage of individuals with ASD³.

Large-scale genetic studies have revealed hundreds of risk genes linked to ASD. ASD-associated genes have been shown to contribute to brain development, neuronal activity, signaling, transcription regulation, and synaptic function⁴. Synapse-related risk genes in ASD encode proteins involved in the formation, stabilization, and maintenance of functional synapses, including cell-adhesion proteins (neuroligins, neurexins, and cadherins), synaptic vesicle cycling proteins SYN1 and SYN2, ion transport proteins such as SCN2A, postsynaptic density proteins SHANK3 and SYNGAP1, and many others³.

Multiple studies have revealed an increased number of de novo mutations in regulatory elements of ASD risk genes in patients ^5–7. Susceptibility genes impacting transcription and chromatin-remodeling pathways include MeCP2, UBE3A, chromodomain helicase DNA binding protein 8 (CHD8), activity-dependent neuroprotector homeobox (ADNP), pogo transposable element derived with ZNF domain (POGZ), fragile X mental retardation protein (FMRP), and RNA binding forkhead box (RBFOX) genes³.

Mutations in ASD-related genes have been shown to affect three key cellular pathways: synaptic function, translation, and WNT signaling. These pathways are interconnected through neuronal activity. Wnt signaling regulates key transcriptional programs that affect neuronal maturation and neural circuit formation, which are also dependent on synaptic activity during development. Localized translation at the synapse underlies synaptic plasticity and cognition, whereas synaptic translation is stimulated by synaptic activity⁴.

Early identification and support for individuals with ASD can improve their outcomes, but specific tools are needed to individualize treatment. Routine use of biomarkers could potentially transform clinical care for patients with ASD by identifying clinically meaningful subgroups within highly heterogeneous populations to allow for more precise, individualized medical care⁸.

Emerging research on potential biomarkers in ASD encompasses genetic, biochemical, metabolomic, immune, and oxidative stress markers as well as neuroimaging, electrophysiologic, physical, and behavioral characteristics.

Biochemical markers include neurotransmitters, hormones, and markers of immune function and inflammation. For example, studies have reported elevated whole-blood serotonin and decreased plasma melatonin levels in individuals with ASD compared to controls^9–11. Furthermore, one study revealed that combined analysis of serotonin, N-acetylserotonin, and melatonin levels could differentiate individuals with autism from controls with 80% sensitivity and 85% specificity¹¹.