Gaedigk, Andrea

The Clinical Pharmacogenetics Implementation Consortium (CPIC) TPMT/NUDT15 Pharmacogene Curation Expert Panel (PCEP) conducted a comprehensive review of clinical, laboratory, and computational evidence to determine the clinical function assignments for TPMT and NUDT15 star alleles. These genes are critical for the metabolism of thiopurines, which are widely used in the treatment of cancer and autoimmune disorders. Standardized allele function assignment is essential for predicting metabolizer phenotypes and pharmacogenetics‐guided thiopurine dosing. The work presented here includes the first designation of decreased function alleles for both TPMT and NUDT15 , reflecting new clinical data that demonstrate partial loss of enzymatic activity and reduced dose tolerance. The panel also reclassified several alleles previously assigned uncertain or unknown function. The functional assignments were informed by a standardized framework incorporating clinical data, such as thiopurine tolerance and toxicity, as well as in vitro protein activity, ex vivo enzymatic measurements, and in silico variant effect prediction tools. These updates enhance the precision of genotype‐to‐phenotype mapping and support more personalized thiopurine therapy across diverse patient populations.

AbstractThe DPYD gene encodes dihydropyrimidine dehydrogenase, the rate‐limiting enzyme for the metabolism of fluoropyrimidines 5‐fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129‐5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single‐nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function‐altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129‐5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129‐5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false‐positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129‐5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus and a comprehensive summary of structural variation. CYP2D6 contributes to the metabolism of numerous drugs and, thus, genetic variation in its gene impacts drug efficacy and safety. To accurately predict a patient's CYP2D6 phenotype, testing must include structural variants including gene deletions, duplications, hybrid genes, and combinations thereof. This tutorial offers a comprehensive overview of CYP2D6 structural variation, terms, and definitions, a review of methods suitable for their detection and characterization, and practical examples to address the lack of standards to describe CYP2D6 structural variants or any other pharmacogene. This PharmVar tutorial offers practical guidance on how to detect the many, often complex, structural variants, as well as recommends terms and definitions for clinical and research reporting. Uniform reporting is not only essential for electronic health record‐keeping but also for accurate translation of a patient's genotype into phenotype which is typically utilized to guide drug therapy.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and, thus, can impact drug efficacy and safety. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).