Prevalence of CYP2D6 structural variation in large retrospective study

CYP2D6 is a highly polymorphic gene with clinically important structural variations. Commonly, only exon 9 is assayed on clinical pharmacogenomics panels, as it allows for accurate functional characterization even in the presence of a CYP2D6::CYP2D7 conversion. However, this method does not capture CYP2D7::CYP2D6 (CYP2D6*13) conversions, possibly leading to inaccurate phenotype assignment. The study's purpose was to determine the frequency of structural variations in CYP2D6 utilizing multiple copy number variation (CNV) assay locations to quantify the potential impact on clinical phenotype classification. A retrospective analysis was conducted of de-identified pharmacogenomics data submitted through the Translational Software, Inc. platform. Samples with CYP2D6 CNV data for exon 9 and at least one additional CNV location (5 ' UTR, exon 1, intron 2, exon 5 or intron 6) were included. CYP2D7::CYP2D6 and CYP2D6::CYP2D7 conversions were classified according to PharmVar nomenclature. The CYP2D6 copies were capped at four total copies to account for assay limitations in detecting more than four copies. A total of 106,474 samples were included for analysis. CYP2D7::CYP2D6 conversions were present in approximately 2.44% of samples, and 5.84% of samples had CYP2D6::CYP2D7 conversions. Many samples did not have a CYP2D7 conversion detected (91.5%; 97,462/106,474). A full gene deletion was detected in 0.15%, and 5.98% had a duplication or multiplication present. This retrospective study underscores the importance of testing more than one CNV site for CYP2D6. Over 2% of patients were found to have a CYP2D7::CYP2D6 conversion. This translates into potentially misclassified phenotype classification and incongruent clinical recommendations.