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Test Catalog

Test ID: 2D6CV    
Cytochrome P450 2D6 (CYP2D6) Comprehensive Cascade, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Providing information relevant to tamoxifen, codeine, and tramadol, as well as other medications metabolized by CYP2D6

 

Determining the exact genotype when other methods fail to generate this information or if genotype-phenotype discord is encountered clinically

 

Identifying exact genotyping when required (eg, drug trials, research protocols)

 

Identifying novel variants that may interfere with drug metabolism

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

Testing is done in 2 tiers when needed. Tier 1 uses a PCR-based 5'-nuclease assay to determine the variants present. All samples also have copy number determined by PCR-based 5'-nuclease assay. Testing in tier 1 allows for the detection of all common CYP2D6 variants (eg, *2, *3, *4, *5, *6, *7, *8, *9, *10, *17, *29, *35, *41) and rarer alleles such as *11, *12, *14A, *14B, and *15. Duplications and multiplications of alleles are also identified. Unitary and tandem CYP2D7-2D6 (*13) alleles and CYP2D6-2D7 (eg, *4N, *36, and *68) alleles can also be detected. Tier 2 testing involves sequencing using fluorescent dye-terminator chemistry and is only done if tier 1 testing results are ambiguous. Approximately 3% of samples require tier 2 testing.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

Tier 2 testing will be performed only if an ambiguous phenotype is identified by tier 1 testing. The number of sequencing tests needed to determine the phenotype will vary depending on the tier 1 result.

 

See CYP2D6 Comprehensive Cascade Testing Algorithm in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The cytochrome P450 (CYP) family of enzymes is a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of the CYP enzymes, CYP2D6, is wholly or partially responsible for the metabolism of many commonly prescribed drugs.

 

The CYP2D6 gene is highly variable with over 100 named alleles. The gene may be deleted, duplicated, and multiplied, and can have multiple sequence variations. In addition, some individuals have genes that are hybrids of CYP2D6 and the CYP2D7 pseudogene. Some individuals have CYP2D6 variants that result in synthesis of an enzyme with decreased or absent catalytic activity. These individuals may process CYP2D6-metabolized medications more slowly. CYP2D6 duplications and multiplications involving active alleles may result in ultrarapid metabolism of CYP2D6-metabolized drugs. CYP2D6 genotype results are used to predict ultrarapid, rapid, normal (extensive), intermediate to normal (extensive), intermediate, poor to intermediate, and poor metabolizer phenotypes.(See Table 1)

 

Table 1. Enzyme Activity of Individual Star Alleles

Enzyme Activity

Examples of CYP2D6 star alleles

Normal (extensive) metabolism

*1, *35

Intermediate to normal activity

*2A

Decreased activity

*2, *9, *10, *14B, *17, *29, and *41

Negligible activity

*36

No or null activity

*3, *4, *4N, *5, *6, *7, *8, *11, *12, *13, *14A, *15, *68

 

CYP2D6 phenotype is predicted based upon the number of functional, partially functional, and nonfunctional alleles present in a sample.

 

Phenotyping was derived from the Human Cytochrome P450 (CYP) Allele Nomenclature Committee website and the PharmGKB website for the related Clinical Pharmacogenetics Implementation Consortium guidelines.

 

There are instances where a phenotype prediction is not categorical and, in these instances, a range of possible phenotypes will be given. It should be noted that other laboratories may use different phenotype prediction methods as there is no consensus on this at this time. However, the method used here represents the findings of the majority of literature available at this time. Individuals without a detectable gene alteration will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2D6 *1/*1.

 

Drugs that are metabolized through CYP2D6 may require dosage adjustment based on the individual patient's genotype. Patients who are poor metabolizers may require lower than usual doses to achieve optimal response in the case of drugs that are inactivated by the CYP2D6 enzyme and higher than usual doses in the case of drugs that are activated by CYP2D6 enzyme. Alternatively, patients who are ultrarapid metabolizers may benefit from increased doses in the case of drugs that are inactivated by CYP2D6 enzyme and lower doses in the case of drugs that are activated by CYP2D6. In the absence of clear guidance from FDA on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism may benefit by switching to comparable alternate medications not primarily metabolized by CYP2D6 or by therapeutic drug monitoring where applicable.

 

Overall, this test provides a comprehensive CYP2D6 genotype result for patients, ensuring a more accurate phenotype prediction. This assay has clinical significance for patients taking or considering medications activated (eg, codeine, tramadol, and tamoxifen) or inactivated (eg, antidepressants and antipsychotics) by the CYP2D6 enzyme.

 

Sequential tier testing associated with this test will be initiated until the least ambiguous phenotype possible is determined.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

A comprehensive interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

A comprehensive interpretive report will be provided that combines the results of all tier testing utilized to obtain the final genotype.

 

The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Pharmacogene Variation (PharmVar) Consortium.(1)

 

For the CYP2D6 Copy Number Variation assay, the reportable copy number range is 0 to 4 copies for each of the CYP2D6 region assessed.

 

Novel variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive comments detailing their potential or known significance.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Rare variants may be present that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings (phenotype), additional testing should be considered.

 

Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.

 

CYP2D6 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP2D6 status.

 

This method may not detect all CYP2D6 variants that result in altered CYP2D6 activity. Therefore, absence of a detectable variant does not rule out the possibility that a patient has altered CYP2D6 metabolism due to other CYP2D6 variants that cannot be detected with this method. Furthermore, when 2 or more variants are identified, the cis-/trans- status (whether the variants are on the same or opposite chromosomes) is not always known.

 

A complicating factor in correlating CYP2D6 genotype with phenotype is that many drugs or their metabolites are inhibitors of CYP2D6 catalytic activity. Selective-serotonin reuptake inhibitors (SSRIs), as well as some tricyclic antidepressants (TCAs) and other drugs, may reduce CYP2D6 catalytic activity. Patients in all metabolizer categories, except poor metabolizer, may have CYP2D6 enzyme activity inhibited by a variety of medications or their metabolites. Consequently, an individual may require a lower medication dose than predicted by genotyping alone. It is important to interpret the results of testing in the context of other coadministered drugs.

 

CYP2D6 alleles with decreased function may metabolize different drugs at different rates, ranging from normal to poor, but the literature on this is incomplete at this time.

 

This test is not designed to provide specific dosing or drug selection recommendations and is to be used as an aid to clinical decision making only. Drug-label guidance should be used when dosing patients with medications regardless of the predicted phenotype.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Pharmacogene Variation Consortium database. Accessed 08/27/2018. Available at www.pharmvar.org/gene/CYP2D6

2. Black JL, Walker DL, O'Kane DJ, Harmandayan M: Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction. Drug Metab Dispos 2012;40(1):111-119

3. Goetz MP, Rae M, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312-9318

4. Kircheiner J, Nickchen K, Bauer M, et al: Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004;9:442-473

5. Crews KR, Gaedigk A, Dunnenberger HM, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2011 Feb;91(2):321-326

6. Hicks JK, Swen JJ, Thorn CF, et al: Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013 May:93(5):402-408

Special Instructions Library of PDFs including pertinent information and forms related to the test