Moyer, AM

Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines. Decreased or no‐function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines. Genetic variants in these genes are present in all world populations; however, their frequency varies by ancestry. In this updated guideline, we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes, including for individuals with variants in both genes (updates on www.clinpgx.org ).

Complement-mediated hemolytic uremic syndrome (CM-HUS), commonly referred to as atypical HUS, is a rare thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway, typically triggered by a “two-hit” mechanism. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage, most commonly affecting the kidneys. While our understanding of the complement system has advanced significantly, CM-HUS remains a complex, heterogeneous disorder influenced by a spectrum of genetic variants, risk haplotypes, and acquired factors such as anti-factor H autoantibodies. This review highlights the current knowledge of CM-HUS pathogenesis, focusing on genetic variants in regulatory and activating proteins of the complement system. We also discuss the diagnostic complexity posed by incomplete penetrance, overlapping phenotypes, and limitations of genetic and functional assays. Emerging ex-vivo assays and complement biomarkers are explored as tools for refining diagnosis and risk stratification. The use of complement inhibitors such as eculizumab and ravulizumab has significantly improved renal outcomes and survival. This review provides a comprehensive, clinically grounded update on the genetics, pathophysiology, diagnostics, and therapeutic considerations in CM-HUS, aiming to provide clinicians and researchers with a deeper understanding of this complex, complement-driven disease.

Abstract Background DPYD testing can identify patients at risk for severe toxicity when a standard fluoropyrimidine antineoplastic dose is prescribed. Sequencing-based methods detect rare variants, which require classification. Methods DPYD sequencing results over a 9-year period through to 2024 were analyzed. The dataset was filtered to calculate the positive test rate for different genotyping strategies, including targeted analysis of the Association for Molecular Pathology (AMP) Tier 1 and 2 recommended alleles, and as compared to sequencing. Variant classifications based on the laboratory’s clinical protocol were compared to ClinVar classifications and designations by the Clinical Pharmacogenetics Implementation Consortium (CPIC) expert panel. Results A DPYD variant was reported in 12.79% (896/7003) of those tested, with 2.53% (170/7003) of all reports including a variant of uncertain significance. Had only AMP Tier 1 or both Tier 1 and 2 been tested, 9.30% and 9.44% of patients would have received a positive report, respectively. Among the 281 unique, non-Tier 1/Tier 2 variants encountered during sequencing, >80% were not classified by the CPIC expert panel, while >48% were not reported in ClinVar. Variant classifications by our laboratory and those in ClinVar were generally concordant with the CPIC expert panel, despite the lack of a standardized classification system. Conclusions While AMP Tier 1 genotyping would have identified most patients at risk for fluoropyrimidine toxicity, sequencing is more comprehensive, identifying 26% more reportable variants compared to targeted genotyping. A standard framework for pharmacogenomic variant classification could facilitate consistent variant classification and a transition from targeted genotyping to sequencing.

ABSTRACT Major depressive disorder (MDD) is a substantial public health challenge. Pharmacogenomics (PGx), which identifies genetic variations that predict drug treatment outcomes, may have utility for clinical practice, but adequate representation of all populations is needed. As precision medicine in psychiatry moves towards the use of Artificial Intelligence (AI) and Machine Learning (ML) to predict treatment outcomes using PGx data, representation of diverse populations will be especially important in order to mitigate algorithmic bias and achieve equitable and generalizable findings. This work sought to quantify population diversity in pharmacogenomic studies of MDD through a systematic review. Data from 390 MDD antidepressant PGx studies were extracted from 5739 articles screened. Studies summarized were predominantly conducted in Europe, East Asia, and North America. Across all global studies, the study population comprised 57.3% White, 36.4% Asian, 1.7% Black, 3.5% Hispanic/Latino, and 0.1% Native American or Indigenous participants. Only sixty‐three (16.2%) studies included Black or Latino/Hispanic patients. Additionally, Black, Asian, Hispanic/Latino, and American Indian/Alaska Native populations were statistically underrepresented in U.S. study populations when compared to national census data, while Asian and Black populations were underrepresented in the United Kingdom. The overrepresentation of participants from a limited number of countries combined with the underrepresentation of Black and Hispanic/Latino populations could impact the extent to which pharmacogenomic testing and associated AI/ML‐based PGx tools could individualize antidepressant medication regimens for treating MDD.

Barriers to incorporating pharmacogenetics into routine clinical practice in the United States are well documented. Initial surveys by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2009 and 2010 identified barriers across four key domains that have hindered the widespread adoption of clinical pharmacogenetic testing. These are presented verbatim as: (i) absence of a definition of the processes required to interpret genotype information and to translate genetic information into clinical actions; (ii) need for recommended drug/gene pairs to implement clinically now; (iii) clinician resistance to consider pharmacogenetic information at the bedside; and (iv) concerns about test costs and reimbursement. Over time, many of these challenges have been overcome, and clinical pharmacogenetic testing has subsequently reached broader implementation. Despite this progress, several barriers remain that block further adoption. This narrative review used authors' expertise and experience to identify and describe current barriers to pharmacogenetic implementation across seven domains in the United States: equity and inclusion; guidelines and supporting evidence; regulatory agency oversight; payer coverage and insurance; availability of quality pharmacogenetic tests; electronic health records; and provider and patient education. Within each domain, it revisits past successes and challenges and explores remaining barriers. We also propose solutions to address ongoing challenges across these domains, including further expansion of recommendations beyond pharmacogenetic‐specific guidelines, standards for designing clinical decision support tools, and broader pharmacogenetics education. Addressing these remaining obstacles directs work to enable broader adoption of clinical pharmacogenetic implementation to ultimately improve patient outcomes.

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.

Background: Adequate response to moderate (conscious) sedation varies significantly between individuals. Polymorphisms in genes encoding drug metabolizing enzymes can lead to inter-individual variability in drug efficacy, potentially influencing sedation requirements during endoscopic procedures. Objectives: The aim of this study was to assess the potential role of inter-individual variation in inherited polymorphisms of drug-metabolizing enzymes, cytochrome P450 (CYP450), specifically CYP3A4 and CYP3A5, in sedation requirements for outpatient endoscopic procedures. Methods: A retrospective analysis of sedation requirements and pharmacogenomics data in 106 unique patients who received outpatient esophagogastroduodenoscopy (EGD), colonoscopy, or both between December 2011 and February 2019 was conducted. Patients were divided into two groups based on their sedation requirements during endoscopy (high vs. normal sedation). Results: Patients with reduced a CYP2C19 metabolism (poor + intermediate metabolizers) (odds ratio [OR] = 0.38, 95% confidence interval [CI]: 0.16–0.91, p = 0.03), poor CYP3A5 metabolism (OR = 0.25, 95% CI: 0.095–0.65, p = 0.0046), and poor UGT1A1 (OR = 2.76, 95% CI: 1.07–7.13, p = 0.08) had higher odds of requiring normal sedation compared to those with CYP2C19 increased metabolism, CYP3A5 intermediate metabolism, and UGT1A1 intermediate metabolism. Conclusion: Information about inter-individual variation in (CYP450) genes may be useful for determining the sedation requirements for outpatient endoscopic procedures. We found that patients with reduced CYP2C19 metabolism, poor CYP3A5 metabolism, and poor UGT1A1 metabolism were more likely to require normal sedation requirements during outpatient endoscopic procedures.

CYP2D6 duplication has important pharmacogenomic implications. Reflex testing with long-range PCR (LR-PCR) can resolve the genotype when a duplication and alleles with differing activity scores are detected. We evaluated whether visual inspection of plots from real-time-PCR-based targeted genotyping with copy number variation (CNV) detection could reliably determine the duplicated CYP2D6 allele. Six reviewers evaluated QuantStudio OpenArray CYP2D6 genotyping results and the TaqMan Genotyper plots for seventy-three well-characterized cases with three copies of CYP2D6 and two different alleles. Reviewers blinded to the final genotype visually assessed the plots to determine the duplicated allele or opt for reflex sequencing. Reviewers achieved 100% accuracy for cases with three CYP2D6 copies that they opted to report. Reviewers did not request reflex sequencing in 49–67 (67–92%) cases (and correctly identified the duplicated allele in each case); all remaining cases (6–24) were marked by at least one reviewer for reflex sequencing. In most cases with three copies of CYP2D6, the duplicated allele can be determined using a combination of targeted genotyping using real-time PCR with CNV detection without need for reflex sequencing. In ambiguous cases and those with >3 copies, LR-PCR and Sanger sequencing may still be necessary for determination of the duplicated allele.