What Genetic Testing is Available for Neurodevelopmental Disorders?

Where do I start?

Why might genetic testing be relevant for ASD? Well, there are over 1100 genes are associated with ASD susceptibility across several chromosomes, many falling on the 7, 15, 22, and X chromosomes. Genetic testing can inform up and coming interventions that may improve physical and neuro-cognitive health. There are several different genetic testing and processes available. I should note though that the same person may be diagnosed with autism OR a genetic condition first or only (e.g., phelan-mcdermid/SHANK3, fragile X/FMR1), depending on which clinical provider is seen and which tests are run.

So basically there are two main types of testing, more specific and more generalized. So let’s start with the specific first. One option is the candidate gene approach or gene-targeted testing to identify potentially genetic abnormalities based on clinical studies or experimental evidence (often animal studies) used to identify cellular abnormalities in ASD or any other condition. On type of test is a chromosomal microarray analysis (CMA), which can look for CNVs (chromosome rearrangements), often a first-line genetic testing. Single-gene testing (SGT)- looks for deletions and duplications of singular genes, while a multigene panel (MP) looks for genes specific to a certain genetic/medical condition (in this case ASD). There is also karyotype screening (KS) which looks for rare chromosomal translocations. And finally you may have heard of FISH testing, or Fluorescence In Situ Hybridization, which is similar to Karyotype test, but pinpoints specific or smaller chromosomal abnormalities, revealing their location and number, crucial for diagnosing genetic disorders with microdeletions.

Now to the more generalized types of genetic testing, comprehensive genomic testing. The first is whole genome sequencing, which examines the whole genome for both gene and chromosome variants, which can provide detailed information on cellular and molecular pathways dysregulated in ASD. These look to identify of disease-modifying genes often via the Genome-Wide Association Study (GWAS) Genome sequencing- improved detection of CNVs and chromosomal rearrangements. On the other hand, whole exome sequencing is not reliant upon a hypothesis for the etiology of a disorder. It is an approach to selectively sequence the coding regions of a genome to uncover rare or common variants (sometimes deletions or duplications, but not on specific genes) associated with a disorder or phenotype and can help to detect mutations and denote variants in ASD affected and unaffected individuals. Now typically the treating doctor or geneticist will decide which types of genetic testing to order, depending on what genetic profile might be suspected, and/or based on the specific symptom presentation.

Once the genetic profile is established (or somewhat established) it may be possible to intervene in an effort to “correct” for these genetic abnormalities. Personalized medicine is the idea that the individual characteristics of each patient are taken into account, as each patient responds differently to specific treatments due to genetic background/environment/lifestyle factors. Pharmacogenomics (gene sight, clarity X, genomind) may advance personalized medicine in ASD, the goal of PGx is to give the right psychotropic at the right dose and the dosing guidelines for the neurotypical population only gives approximations when using psychotropic medications in autistics. PGx may be promising in terms of targeting certain genes to increase effectiveness of Risperdal and Abilify, then only two on-label medications to treat symptoms of autism. We may be able analyze these genes to inform clinicians in terms of dosing and treatment options, looking for biomarker development via mRNA.

One area of potentially promising research is to administer lysine-specific demethylase 1 (LSD1) such as Vafidemstat (oral capsules; phase 2 clinical trials), which per the early research, may be helpful to improve cognition and reduce agitation. A very new drug, LMK235 (administered through subcutaneous injection, under the skin, HDAC5 inhibitor, preclinical trials, animals only) to normalize histone acetylation and restore GABA signaling in the prefrontal cortex, improving social skills. Modulating glutamate receptors (drug: AMPAR-PAM, administered orally, phase 3 clinical trials), normalize social deficits and RRBs, improved synaptic transmission (may improve learning and memory), though more research needed. Similarly, modulating glycine receptors (drug: D-cycloserine, phase 3 clinical trials) partial agonist at NMDAR, social learning, variable results. CRISPR-Cas9 gene editing, which is precise genetic adjusting, has shown to improve social interaction and reduced RRBs, via injected RNA. There is the potential to engineer pre-clinical models to understand the molecular and cellular pathways in ASD. Additionally, there was some benefit from intranasally (through the nose) administered insulin (improved motor, language, and cognition functions), and from oral zinc supplementation, while there was no benefit from intranasal oxytocin.

So hopefully this clarifies a bit in terms of the different options for genetic testing, and why it may be beneficial to undergo more than one type of genetic testing or exploration. Additionally, the benefits of genetic testing are now potentially much more significant than they were in the past.