Prevalence of CYP2D6 structural variation in large retrospective study

Area of Science:

• Pharmacogenomics
• Clinical Genetics
• Molecular Diagnostics

Background:

• CYP2D6 gene variations significantly impact drug metabolism and clinical outcomes.
• Current pharmacogenomic testing often relies on single-site assays (e.g., exon 9) for CYP2D6, which may miss critical structural variations.
• CYP2D7::CYP2D6 conversions can lead to inaccurate CYP2D6 phenotype assignment.

Purpose of the Study:

• To determine the frequency of CYP2D6 structural variations using multiple copy number variation (CNV) assay locations.
• To quantify the impact of these variations on clinical phenotype classification.
• To highlight the limitations of single-site CNV analysis for CYP2D6.

Main Methods:

• Retrospective analysis of de-identified pharmacogenomics data from 106,474 samples.
• Utilized CYP2D6 CNV data from exon 9 and at least one additional location (5'UTR, exon 1, intron 2, exon 5, or intron 6).
• Classified CYP2D7::CYP2D6 and CYP2D6::CYP2D7 conversions according to PharmVar nomenclature, capping copies at four.

Main Results:

• CYP2D7::CYP2D6 conversions were identified in 2.44% of samples.
• CYP2D6::CYP2D7 conversions were present in 5.84% of samples.
• Gene deletions occurred in 0.15%, and duplications/multiplications in 5.98% of samples.

Conclusions:

• Testing multiple CNV sites for CYP2D6 is crucial for accurate genetic assessment.
• Over 2% of patients exhibited CYP2D7::CYP2D6 conversions, potentially leading to misclassified phenotypes.
• Inaccurate phenotype classification can result in incongruent clinical recommendations, emphasizing the need for comprehensive CYP2D6 structural variant analysis.