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Test ID: 2D6CB Cytochrome P450 2D6 (CYP2D6) Comprehensive Cascade, Blood

Useful For

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

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
2D6CN CYP2D6 Copy Number Variation, B No, (Bill Only) No
2D6X1 2D6CN Plus One Sequence No, (Bill Only) No
2D6X2 2D6CN Plus Two Sequences No, (Bill Only) No
2D6X3 2D6CN Plus Three Sequences No, (Bill Only) No
2D6X4 2D6CN Plus Four Sequences No, (Bill Only) No
2D6X5 2D6CN Plus Five Sequences No, (Bill Only) No
2D6X6 2D6CN Plus Six Sequences No, (Bill Only) No

Reporting Name

CYP2D6 Genotype Cascade, B

Specimen Type

Whole Blood EDTA


Advisory Information


This test is not for use in assessing for autoimmune hepatitis. Autoantibodies for CYP2D6 enzyme are found in many cases of autoimmune hepatitis; order LKM / Liver/Kidney Microsome Type 1 Antibodies, Serum for autoimmune hepatitis assessment.



Specimen Required


Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.


Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)
  Refrigerated 

Clinical Information

The cytochrome P450 (CYP) family of enzymes is responsible for primary metabolism of many drugs. CYP450s are 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 such as some analgesics, anticonvulsants, antidepressants, antipsychotics, antiemetics, antihypertensives, antiestrogens, antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants, sympathomimetic and other drug classes.

 

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 altered CYP2D6 variants that result in synthesis of enzyme devoid of catalytic activity, or an enzyme with diminished catalytic activity. These individuals may process CYP2D6-metabolized medications more slowly depending upon the gene variant found on each chromosome. CYP2D6 duplications and multiplications involving active alleles may result in ultrarapid metabolism of CYP2D6-metabolized drugs. CYP2D6 genotype results are used to predict ultrarapid, ultrarapid to extensive (normal), extensive (normal), extensive (normal) to intermediate, intermediate, intermediate to poor, 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. (see Table 2)

 

Table 2. Phenotype Assignment of CYP2D6

Predicted Drug Metabolizer Phenotype**

Without Gene Duplication

With Gene Duplication

UM

2 increased activity alleles

3 normal and/or increased activity alleles

EM to UM

A combination of 1 normal activity allele with 1 increased activity allele

A combination of 2 normal alleles with 1 decreased activity allele

EM

2 normal activity alleles; a combination of one increased activity allele with one decreased allele

A combination of 2 normal alleles with 1 null allele; a combination of 1 normal allele with 2 decreased activity alleles

IM to EM

 A combination of 1 normal activity allele with 1 decreased activity allele; a combination of 1 increased activity with 1 null allele

1 increased activity allele with 2 null alleles, 3 decreased activity alleles

IM

1 normal activity allele with 1 null activity allele; 2 decreased activity alleles

1 normal allele with 2 or more null alleles, 2 decreased activity alleles with 1 null allele.

PM to IM

A combination of 1 decreased activity allele with 1 null allele

1 decreased activity allele with 2 null allele

PM

Only null alleles detected

* 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.

**Ultra-Rapid Metabolizer, UM; Extensive Metabolizer, EM; Intermediate Metabolizer, IM; Poor Metabolizer, PM

 

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.

 

Dosing drugs that are metabolized through CYP2D6 may require 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 another comparable drugs that is 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.

 

The different tiers associated with the CYP2D6 Cascade will be sequentially initiated until a complete genotype is determined.

Reference Values

A comprehensive interpretive report will be provided.

Interpretation

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 Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(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, please see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Clinical Reference

1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available at www.cypalleles.ki.se/cyp2d6.htm

2. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

3. Black JL 3rd, 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

4. 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

5. 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

6. 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

7. 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

Day(s) and Time(s) Performed

Monday, Thursday; 8 a.m.

Analytic Time

8 days (not reported Saturday or Sunday)

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

2D6CB

81226-CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)

 

2D6CN

81479-Unlisted molecular pathology procedure (if appropriate)

 

2D6X1

81479-Unlisted molecular pathology procedure (if appropriate)

 

2D6X2

81479-Unlisted molecular pathology procedure (if appropriate)

 

2D6X3

81479-Unlisted molecular pathology procedure (if appropriate)

 

2D6X4

81479-Unlisted molecular pathology procedure (if appropriate)

 

2D6X5

81479-Unlisted molecular pathology procedure (if appropriate)

 

2D6X6

81479-Unlisted molecular pathology procedure (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
2D6CB CYP2D6 Genotype Cascade, B 40425-1

 

Result ID Test Result Name Result LOINC Value
34557 CYP2D6 Phenotype 72880-8
34556 CYP2D6 Star Alleles 40425-1
34553 CYP2D6 Interpretation 69047-9
34554 Reviewed by No LOINC Needed

Method Name

Tier 1: Polymerase Chain Reaction (PCR) with Allele-Specific Primer Extension (ASPE)

Tier 2: Real-Time Quantitative PCR
Tier 3: PCR followed by DNA Sequence Analysis

Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

Cardiovascular Test Request Form (T724) (http://www.mayomedicallaboratories.com/it-mmfiles/cardiovascular-request-form.pdf).

Neurology Specialty Testing Client Test Request (T732) (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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