Genomics as a Clinical Decision Support Tool: Successful Proof of Concept for Improved ASD Outcomes

Abstract

Considerable evidence is emerging that Autism Spectrum Disorder (ASD) is most often triggered by a range of different genetic variants that interact with environmental factors such as exposures to toxicants and changes to the food supply. Up to 80% of genetic variations that contribute to ASD found to date are neither extremely rare nor classified as pathogenic. Rather, they are less common single nucleotide polymorphisms (SNPs), found in 1–15% or more of the population, that by themselves are not disease-causing. These genomic variants contribute to ASD by interacting with each other, along with nutritional and environmental factors. Examples of pathways affected or triggered include those related to brain inflammation, mitochondrial dysfunction, neuronal connectivity, synapse formation, impaired detoxification, methylation, and neurotransmitter-related effects. This article presents information on four case study patients that are part of a larger ongoing pilot study. A genomic clinical decision support (CDS) tool that specifically focuses on variants and pathways that have been associated with neurodevelopmental disorders was used in this pilot study to help develop a targeted, personalized prevention and intervention strategy for each child. In addition to an individual’s genetic makeup, each patient’s personal history, diet, and environmental factors were considered. The CDS tool also looked at genomic SNPs associated with secondary comorbid ASD conditions including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections/pediatric acute-onset neuropsychiatric syndrome (PANDAS/PANS). The interpreted genomics tool helped the treating clinician identify and develop personalized, genomically targeted treatment plans. Utilization of this treatment approach was associated with significant improvements in socialization and verbal skills, academic milestones and intelligence quotient (IQ), and overall increased ability to function in these children, as measured by autism treatment evaluation checklist (ATEC) scores and parent interviews.

A Personalized Approach to Evaluating and Treating Autism Spectrum Disorder

“…By analyzing the genome of a well-known professor with high-functioning ASD, Dr Temple Grandin, insight into how interactions between a complexity of genetic variations may result in the ASD phenotype is discussed in one article [7]. In another article, a genomic clinical decision support tool that focuses on relatively common DNA variants in pathways that can be targeted for treatment to improve symptoms is described along with several cases successfully treated using this tool [8]. In many cases, the complexity of genetic changes (as well as potential environmental interactions) is not clear.…”

“…In a large national survey of 1286 participants across the US, several nutraceuticals, including folate and cobalamin, were found to be rated by families to have greater benefits than a similar survey of psychiatric and seizure medications [19]. Another study demonstrates how examining genetic variations can help consider targeting common nutraceutical treatments on a personalized basis [8].…”

“…Perhaps most apparent, these articles underline the primacy of mitochondria in ASD, including oxidative stress and redox regulation, which are themselves major functions of mitochondria. Although the connection between ASD and this important cellular organelle is hardly new, this collection of papers serves to demonstrate the ubiquitous nature of the connection, which ranges from mitochondrial aspects in the prenatal and environmental risk factors/exposures [2,3,8] to biomarkers/metabolites [5,8,[12][13][14][15][16], enzymology [12], and the positive response to therapy, at least in part targeting the mitochondria [8,11,12,15,16,18,19].…”

“…Many papers also relate to another potential etiology of ASD, particularly the immune system, in which multiple interactive domains are highlighted, including innate immunity, immune deficiency, autoimmunity, inflammation, and mast cell activation [7,8,10,11,15,16]. However, similarly to neurons, leukocytes are highly dependent on energy metabolism, and the connections between energy and immunity are many and important.…”

“…Is ASD itself a result of abnormal mitochondria, with effects on neurons and/or leukocytes-essentially a "Bad Trio" of mitochondrial dysfunction, oxidative stress and redox regulation, and immune system dysfunction [3]? Is there a room for a primary role in pathogenesis for other pathways, including synapses [6][7][8], methylation [8,18], autonomic nervous function [9,20], ion channels [6], hypermobility [9], and microbiome [14], at least in some cases? Or, perhaps, do these concepts work within the mitochondrial hypothesis?…”