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Understanding
Okur-Chung Neurodevelopmental Syndrome

CSNK2A1 Foundation Logo

Understanding
Okur-Chung Neurodevelopmental Syndrome

Science Snapshot – Pharmacogenomics Tests

Author: Ingrid Vallee, PharmD, PhD Student, Scripps Research, CSNK2A1 Foundation Volunteer

Edited by: Gabrielle Rushing, PhD, Chief Scientific Officer, CSNK2A1 Foundation


Note: We suggest reading our Pharmacogenomics overview blog first.

What is PGx testing?

Pharmacogenomic (PGx) tests aim to tailor drug prescriptions by improving efficacy and/or limiting adverse side effects by screening for DNA variants that could modify the body’s response to a drug. A strong association between a variant and a drug response is needed for a test to be relevant. In a previous blog, we discussed the challenges of pediatric testing and PGx due to lack of information (see: https://www.csnk2a1foundation.org/science-snapshot-pharmacogenomics). PGx testing is a rapidly growing field and is constantly updated, thus increasing availability of testing for children and adults. Many PGx tests are already available via home tests, clinical trials, and for research purposes from both public and private initiatives. In this blog, we will review the different kinds of PGx tests available and in which contexts they can be most useful. 

CA Levels of Evidence

PGx is still a relatively novel concept in precision medicine (a form of medicine that uses information about a person's genes, proteins, environment, and lifestyle to prevent, diagnose, or treat disease) intended to facilitate personalized drug prescription. While some evidence is available, we need a better understanding of how to integrate it in everyday medical decision making. PGx databases have gathered information about the level of correlation between gene variants and reaction to drugs. For example, PharmGKB annotates variants with the level of evidence that links drugs and variants. Level 1 evidence has highest correlation and level 4 does not support an association between a variant and a drug1. It is always advised to discuss the possibility of PGx testing with a healthcare provider.


1 Clinical Annotation Levels of Evidence between drug and variant (image from PharmGKB)

PGx testing aims to identify correlations between genetic variants and the way the body processes certain drugs. Many patients with rare diseases are initially diagnosed by whole genome/exome sequencing, theoretically making their entire DNA sequence readily available to interpret for any variant. For privacy purposes, current laws protect patients by preventing sharing of DNA sequencing data with unauthorized parties. As a result, somebody who already had their whole DNA sequenced may have to take a PGx test to gather specific information about how their particular gene variant may affect their response to a particular drug. 


Note: many PGx tests are available for various indications. Here we focus mostly on tests relevant in pediatric diseases with neurological symptoms. 

Point-of-Care versus Large panel testing

Two types of PGx testing currently exist: 


  • Point-of-Care testing is used to determine the body’s reaction to a particular drug in order to adapt the dosage or substitute a different drug to enhance efficacy and/or limit adverse side effects. This testing is used for a specific clinical need and short-term decisions. For example, antidepressants can be processed differently by each individual, partly due to the genetic variants they carry for the gene responsible for breaking down certain antidepressants. If this drug is not adapted to the patient, PGx tests can be conducted to try to identify the cause and adapt the treatment accordingly. The test is targeted towards one gene for one drug and is informative for this specific situation.

    This can also help in urgent, one-time prescription situations where the correlation between the drug and risk of adverse side effects/ dosage issue is well documented. One time testing is cheaper than larger panel testing, but costs can add up if multiple targeted tests are required. For example:


  1. Carbamazepine is a drug that can alleviate neurological symptoms including seizures. There is a well-known hypersensitivity to this drug that can cause severe reactions in people carrying the specific variants for the HLA-B*15 gene, mostly found in populations of Asian ancestry (HLA-B*15:02 and HLA-B*15:11)2. Getting tested for these variants before starting treatment can limit the risk of severe reaction. It can also explain severe unlisted reactions after starting the treatment. 

  2. Tramadol and other Opioid-derived drugs are prescribed as pain relievers. There is a confirmed association between CYP2D6 variants and processing speed of the drug, putting different variant carriers at different risks3,4. Getting tested for variants can avoid over or underdosing. 


  • Large panel PGx testing is a proactive approach where a large panel of variants are tested, and results are kept for future reference in patient care. Sometimes these results are stored in electronic medical records. It is most helpful for patients with chronic diseases taking multiple medications. Instead of targeting one gene/variant, the goal is to test a set of variants that are known to be associated with families of drugs given for medical indications. Note: The tests mentioned below include testing for carbamazepine interaction.

    Within larger panel tests, some are to guide drug prescription, while non-therapeutic tests are for research purposes to increase PGx knowledge. (Note: Non-therapeutic clinical trials are important because they increase general knowledge in an unbiased way; linked are a few examples of ongoing programs for long-term patients in these clinics    5–7). We will cover some of the tests meant to guide drug prescription. Many tests exist and selecting the right test can be done collaboratively with a health provider. Below are a few examples:

    Example 1: the         GeneSight Psychotropic pharmacogenomic test specifically evaluates the impact of one’s genetic signature on certain medications commonly prescribed to treat depression, anxiety, ADHD, and other mental health conditions. The goal is to help alleviate the trial-and-error process of finding the best medication while avoiding side effects for antidepressants and more. The genetic information collected from the test can give insights into dose adjustment, probable efficacy of a drug, and potential side effects8.

    Example 2: the         OneOme RightMed panel covers hundreds of medications to treat a wide range of medical conditions, including cancer, psychiatric conditions, chronic pain and more9.

    Example 3: The         Admera PGxOne Plus panel can be only ordered by healthcare providers and covers multiple therapeutic areas such as psychiatry, pain management and cardiology10.
A diagram of a person taking a pgx test

Summary

Factor Point-of-Care Testing Large panel testing
Timeline of drug need Immediate medication needs Chronic conditions with future medication needs
Cost Lower upfront cost, Expensive repeated testing One-time higher initial cost
Data storage Simple Need support to store and access data
Test Single gene Multiple gene

References

  1. Clinical Annotation Levels of Evidence. PharmGKB https://www.pharmgkb.org/page/clinAnnLevels.
  2. Clinical Annotation for HLA-B*15:02, HLA-B*15:11; carbamazepine; drug reaction with eosinophilia and systemic symptoms, Epidermal Necrolysis, Toxic, Maculopapular Exanthema, severe cutaneous adverse reactions and Stevens-Johnson Syndrome (level 1A Toxicity). PharmGKB https://www.pharmgkb.org/clinicalAnnotation/981419263.
  3. Annotation of CPIC Guideline for tramadol and CYP2D6. PharmGKB https://www.pharmgkb.org/guidelineAnnotation/PA166228101.
  4. Dean, L. & Kane, M. Tramadol Therapy and CYP2D6 Genotype. in Medical Genetics Summaries (eds. Pratt, V. M. et al.) (National Center for Biotechnology Information (US), Bethesda (MD), 2012).
  5. PG4KDS: Clinical Implementation of Pharmacogenetics. St. Jude Care & Treatment https://www.stjude.org/care-treatment/clinical-trials/pg4kds-pharmacogenetics.html.
  6. Center for Individualized Medicine - Pharmacogenomics: RIGHT 10K Study. Mayo Clinic https://www.mayo.edu/research/centers-programs/center-individualized-medicine/research/clinical-studies/right-10k.
  7. Center for Pharmacogenomics and Precision Medicine » Precision Medicine Program » UF Health » University of Florida. https://precisionmedicine.ufhealth.org/research/center-for-pharmacogenomics-and-precision-medicine/.
  8. For Patients. GeneSight https://genesight.com/for-patients/.
  9. Welcome to OneOme - OneOme.com. https://oneome.com/home-international/.
  10. Admera Health PGxOneTM Plus - Clinical Genetic Test - GTR - NCBI. https://www.ncbi.nlm.nih.gov/gtr/tests/567653/.


Image created in BioRender

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