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Pharmacogenomic Actionability in >15,000 Patients with Next-Generation-Sequencing-Enabled Copy Number Variation and Novel Haplotype Detection

Authors Joseph Stanton, Sarah Morris, Raul Torres, Brooke Rhead, Chris Vlangos, Anthony Zhogbi, Jai Patel, Marcus Badgeley

Purpose: Patients diagnosed with major depressive disorder do not consistently achieve adequate symptom reduction. CPIC and FDA have published prescribing recommendations for psychiatric-related medications impacted by pharmacogenomics (PGx) and phenoconversion. There are limited analyses on allele-specific copy number variations (CNVs) and emerging biomarkers such as the CYP2C-TG haplotype. In this study, we evaluated the prevalence of PGx actionability in a large, real-world cohort of patients receiving psychiatric care with established guidelines and emerging biomarkers.

Methods: De-identified records of patients with PGx testing were analyzed in this cross-sectional study to identify the prevalence of implication rates for medication prescribing. Genetic testing was performed using the Tempus nP assay, which uses next-generation sequencing (NGS), and clinical implications were obtained from the FDA and CPIC. We performed NGS-based ancestry inference and novel haplotype imputation using the DNA algorithms ADMIXTURE and GLIMPSE, respectively.

Results: Of 15,099 patients, 65% had a potentially actionable CYP2D6- and/or CYP2C19 phenotype (48% CYP2D6, 33% CYP2C19). Potential actionability was highest in European (66%) and lowest in Asian (51%) ancestries. In 2,235 patients with prior or current psychiatric medications, 364 had clinically actionable phenotypes (16%). Of 4,154 patients with any medication data, 42% had phenoconversion – implying medications may have changed their CYP2D6 phenotype. Among 1,115 (7.4%) patients with CYP2D6 CNVs, phenotype assignment was affected by allele assignment in 344 (2%). CYP2C-TG was identified in 36% of patients, of whom 20% were expected to exhibit increased CYP2C19 metabolism and changes in potential actionability. The majority of patients with available medication data had prescribing actionability according to existing PGx biomarkers and FDA/CPIC guidelines for PGx and phenoconversion (82%). Of the remaining 18% of patients who would be expected to have normal metabolism based on today’s guidelines, 5% harbored a recently described CYP2C-TG biomarker that is potentially actionable. In total, 87% of patients had some source of actionability, and 7% required NGS to identify.

Implications: NGS-enabled PGx testing identified prescribing actionability in 87% of patients. Notably, NGS was necessary to accurately assign 7% of cases with CNV-allele assignment and novel haplotype imputation.