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.

Implementing Pharmacogenomics Testing: Single Center Experience at Arkansas Children's Hospital.

Pharmacogenomics (PGx) is a growing field within precision medicine. Testing can help predict adverse events and sub-therapeutic response risks of certain medications. To date, the US FDA lists over 280 drugs which provide biomarker-based dosing guidance for adults and children. At Arkansas Children's Hospital (ACH), a clinical PGx laboratory-based test was developed and implemented to provide guidance on 66 pediatric medications for genotype-guided dosing. This PGx test consists of 174 single nucleotide polymorphisms (SNPs) targeting 23 clinically actionable PGx genes or gene variants. Individual genotypes are processed to provide per-gene discrete results in star-allele and phenotype format. These results are then integrated into EPIC- EHR. Genomic indicators built into EPIC-EHR provide the source for clinical decision support (CDS) for clinicians, providing genotype-guided dosing.