HOW ARE THE PHARMACOGENOMIC TEST RESULTS DETERMINED AND REPORTED?

MyDNA Life offers pharmacogenomic testing through two NATA accredited laboratories: GenSeq Laboratories (NATA accredited lab No 20082) and Australian Clinical Labs (NATA accredited lab No 3427).

  1. GenSeq Laboratories: DNA is extracted and SNP genotyping is performed using open array technology (Life Technologies QuantStudio 12K). CYP2D6 copy number is established by real time PCR (QuantStudio 6), allowing for quantification of up to 4 copies.
  2. Australian Clinical Labs: DNA is extracted and SNP genotyping is performed using the Agena MassArray platform. CYP2D6 copy number is confirmed by long-range PCR. There are usually only 2 copies for the CYP2D6 gene when it is duplicated, however, there may be more than 2 copies in some cases. Current technical limitations of the test do not allow measurement of the exact gene copy number.

The following alleles are detectable:

 

myDNA medication Test Allele(s)
CYP2D6 *2, *3, *4, *5, *6, *7, *8, *9, *10, *14A, *14B, *17, *29, *36, *41
CYP2C19 *2, *3, *17
CYP2C9 *2, *3
CYP1A2 *1F
CYP3A4 *22
CYP3A5 *3
SLCO1B1 *5 (reported as the C allele at SLCO1B1 rs4149056)
VKORC1 -1639G>A

The *1 allele denotes the absence of any variant and is designated as the wild type. The *1A allele denotes the absence of the *1F variant for CYP1A2. Only a single variant SNP is tested in the CYP3A4, CYP3A5, CYP1A2 and SLCO1B1 genes. The CYP2D6*29 allele is only tested by GenSeq Laboratories.

Terminology for enzyme function phenotype closely aligns with the Clinical Pharmacogenetics Implementation Consortium Term Standardization Project1. We have added subcategories “low normal” and “high intermediate” to accommodate certain CYP2D6, CYP2C19 and CYP2C9 genotypes, as below. Genotype-phenotype assignment is as follows:

myDNA medication Test Phenotype Genotype-phenotype assignment
CYP2D6 Ultrarapid Metaboliser 3 or more normal alleles or
2 or more normal alleles & 1 or more decreased alleles
Normal Metaboliser 2 normal alleles or 1 normal & 1 decreased allele or 1 normal & 2 decreased alleles
Low Normal Metaboliser 1 normal & 1 no function allele
Intermediate 2 decreased alleles or 1 decreased & 1 no function allele
Poor 2 no function alleles
CYP2C19 Ultrarapid Metaboliser 2 increased alleles
Rapid Metaboliser 1 normal & 1 increased allele
Normal Metaboliser 2 normal alleles
High Intermediate Metaboliser 1 no function & 1 increased allele
Intermediate Metaboliser 1 normal & 1 no function allele
Poor 2 no function alleles
CYP2C9 Normal Metaboliser 2 normal alleles
High Intermediate Metaboliser 1 normal / *2 decreased allele
Intermediate Metaboliser 1 normal / *3 decreased allele
Poor 2 decreased alleles
CYP1A2 Ultrarapid Metaboliser (with inducer present) *1F/*1F
Normal Metaboliser *1A/*1A or *1A/*1F
CYP3A4 Normal Metaboliser *1/*1
Intermediate Metaboliser (Provisional assignment) Carrier of 1 or 2 *22 alleles
CYP3A5 Normal Metaboliser *1/*1
Intermediate Metaboliser *1/*3
Poor Metaboliser *3/*3
SLCO1B1 Normal transporter activity TT
Intermediate transporter activity TC
Low transporter function CC ( Equivalent to the *5 allele)
VKORC1 Normal VKORC1 enzyme level G/G
Moderately reduced VKORC1 enzyme level A/G
Significantly reduced VKORC1 enzyme level A/A

Once testing is completed by the lab, the results are sent by secure HL7 messaging to MyDNA Life for reporting. The clinical interpretation report is prepared by a team comprising physicians, pharmacists and molecular geneticists. Interpretation is based on the primary pharmacogenomic literature with reference to the published clinical recommendations of Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG).

Test Limitations

The myDNA medication test detects common variants in 8 genes (6 genes encoding CYP450 drug metabolising enzymes, VKORC1, encoding a protein that partially determines sensitivity to warfarin and SLCO1B1, encoding a drug transporter important for statins). The genes tested in the myDNA medication test have clinically significant associations which have been documented in the peer-reviewed literature and, for some have associated published clinical practice guidelines.

There are important myDNA test limitations to consider:

  1. The test only provides information about medications for which one or more of the eight genes are known to influence medication concentration or response. Therefore, the test cannot determine how individuals respond to all medications in clinical use.
  2. Response to medications is complex and often incompletely understood. The myDNA medication test only looks at one aspect which may affect medication response (i.e. changes in drug concentration due to genetic variation) and this should be considered when interpreting the test. Of note, a “normal” result does not predict that the patient will always respond to a medication and not experience any side effects, and allergic reactions cannot be detected by this genetic test.
  3. The test does not detect all known variants in the genes tested. Only common variants are tested that are present in Caucasian, African and Asian backgrounds. If an individual carries a rare variant or a variant mostly found in other ethnicities, then this variant will not be detected, the allele will be classified as the default or wild type (e.g. *1) and the phenotype may be inaccurate. Only testing the common variants is the practice of most screening molecular genetic testing laboratories around the world.

1. Caudle KE, Dunnenberger HM, Freimuth RR, Peterson JF, Burlison JD, Whirl-Carrillo M, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med. 2017;19(2):215-23.

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