July 2022 – Laboratory Genetics and Genomics and Molecular Pathology

*2Ax2/*17; ultrarapid metabolizer.

The duplicated allele can be determined by follow-up Sanger sequencing or by review of the allelic ratios. Visual assessment of the VIC/FAM signals on the plots suggest that the patient’s points (run in duplicate) are falling toward the *2A allele for both heterozygous alleles. Thus, this patient’s genotype is *2Ax2/*17. Given the duplication of the *2A allele which has an activity score of 1, this patient has a total activity score of 2.5, and an ultrarapid metabolizer phenotype is the appropriate assignment. Such patients will metabolize codeine to its more active metabolite — morphine — at a faster pace and will consequently be at risk for opioid intoxication.

Incorrect: Poor metabolizer

The *5 allele is a full gene deletion, which is not consistent with the results of the copy number assay that revealed a full gene duplication. Furthermore, the variants depicted in the images are not consistent with those present in a *4 allele. Finally, such patients would be unable to achieve the active, pain-relieving morphine in sufficient concentrations and would stand to experience poor pain control for their condition.

Incorrect: Normal metabolizer

Duplication of the *17 allele would have led to an activity score of 2.0, which corresponds to a normal metabolizer phenotype. Based on genetics alone, a normal metabolizer would be expected to respond appropriately to standard dosing.

Incorrect: Intermediate metabolizer

The variants detected and pictured in the images do not correspond to a *4 allele. Additionally, based on genetics alone, an intermediate metabolizer would be predicted to respond to a standard dose, or potentially require an alternate medication for pain control.

References

1. Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther. 2021 Oct;110(4):888-896.
2. https://www.pharmvar.org/gene/CYP2D6; Accessed 5/31/2022.
3. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007 Aug;7(4):257-265.
4. Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A review of the important role of CYP2D6 in pharmacogenomics. Genes (Basel). 2020 Oct 30;11(11):1295.