An 80-year-old woman was discharged from the hospital after an orthopedic procedure. For pain control, codeine was prescribed. The following day the patient was found somnolent in her living room by her family. The primary provider considered a dose adjustment after ordering pharmacogenetic testing for CYP2D6. The CYP2D6 test revealed a full gene duplication and the genetic variants present in the images.
The correct answer is ...
*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.
Mazen Atiq, M.B.B.S.
Resident, Clinical Pathology
Ann Moyer, M.D., Ph.D.
Consultant, Laboratory Genetics and Genomics
Associate Professor of Laboratory Medicine and Pathology, Assistant Professor of Pharmacology
Mayo Clinic College of Medicine and Science