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Detecting CYP2D6 Hybrid Alleles and Preventing Sample Mischaracterization with the MassARRAY® System

Meet Dr. Houda Hachad

Dr. Houda Hachad is an entrepreneurial scientist with deep experience in pharmacology and pharmacogenetics. At the University of Washington, she co-developed a drug interaction database and a pharmacogenetics database. Both leverage revenue-based funding and are widely used by pharmaceutical companies, regulatory agencies, and academic institutions worldwide. She is Chief Scientific Officer at Translational Software, where her team creates easy-to-use PGx reports for physicians.

The Challenge

CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used medications. Not surprisingly, accurate characterization of CYP2D6 copy number is critical to many PGx applications.

However, clinical laboratories may face blind spots in their PGx detection methods. Many technologies require the use of a separate workflow for copy number detection, drastically reducing lab efficiency. Additionally, they cannot detect CYP2D6 hybrid alleles, which can lead to sample mischaracterization.

Depending on ethnicity, up to 37% of individuals possess a non-functional CYP2D6 hybrid allele, in which a portion of the CYP2D6 gene has been replaced with DNA from CYP2D7, rendering it non-functional. Common CYP2D6 copy number detection methods, such as TaqMan PCR, cannot detect these alleles, resulting in pharmacogenetic profile mischaracterization.

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The Solution

Dr. Hachad offers insights and recommendations for overcoming these challenges to achieve a comprehensive CYP2D6 profile and more accurate PGx results.

QWhy is CYP2D6 copy number detection so important to PGx testing?

ACYP2D6 influences the metabolism of around 25% of all commonly used medications, so accurately characterizing it is critical. While characterization of the alleles based on SNPs and INDELs is important, it is incomplete without an understanding of the gene copy number. Without proper characterization of copy number, you cannot properly determine the various phenotypes.

qWhat are CYP2D6 hybrid alleles and how do they affect copy number detection?

aCYP2D6 hybrid alleles are structural variations that change the functionality of the enzyme. These alleles are fairly common. It is essential to distinguish between hybrids and other CYP2D6 alleles to accurately characterize a sample’s metabolizer status. Unfortunately, depending on the technology being used, that can be difficult to do.

QWhy are CYP2D6 hybrid alleles difficult to detect?

A  Most PGx copy number detection methods cannot detect hybrid alleles. They only look at one, two, or maybe three regions on the gene. That is not enough. You need a technology that looks broadly across the gene to catch these structural changes. The VeriDose® CYP2D6 CNV Panel from Agena is a great example of a technology that is well-suited for hybrid allele detection. The single-well panel interrogates 22 points along the gene to identify hybrid alleles and provide accurate copy number callin.

Explore the MassARRAY® for PGx Testing

Download the VeriDose CYP2D6 Panel Brochure: The VeriDose CYP2D6 Panel accurately detects CNVs even in the presence of difficult-to detect hybrid alleles. It interrogates 22 points in 7 regions of the CYP2D6 gene using a single well. This panel can be run simultaneously with genotyping panels, seamlessly integrating genotyping and CNV workflows.

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“ Bottom line, if you are detecting CNV by looking only at a specific region, you are likely missing hybrid alleles. Most PGx copy number detection methods cannot detect hybrid alleles. They only look at one, two or maybe three regions on the gene. That is not enough.

– Dr. Houda Hachad

Pharm.D, M.Res | Chief Scientific Officer
Translational Software

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