Publications by authors named "Victoria M Pratt"

65 Publications

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing.

Genet Med 2021 Dec 19;23(12):2335-2341. Epub 2021 Jul 19.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, University of Florida College of Pharmacy, Gainesville, FL, USA.

Purpose: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.

Methods: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.

Results: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low.

Conclusion: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.
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http://dx.doi.org/10.1038/s41436-021-01269-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633054PMC
December 2021

Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy.

J Mol Diagn 2021 09 10;23(9):1047-1064. Epub 2021 Jun 10.

The Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine and Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.

The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing, and to determine a minimal set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations on a minimal panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories in designing assays for PGx testing. When developing these recommendations, the Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations with regard to PGx testing. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document is focused on clinical CYP2D6 PGx testing that may be applied to all cytochrome P450 2D6-metabolized medications. These recommendations are not meant to be interpreted as prescriptive but to provide a reference guide for clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform.
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http://dx.doi.org/10.1016/j.jmoldx.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579245PMC
September 2021

PharmVar GeneFocus: CYP2C9.

Clin Pharmacol Ther 2021 09 12;110(3):662-676. Epub 2021 Jul 12.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs, including nonsteroidal anti-inflammatory drugs, phenytoin, antidiabetic agents, and angiotensin receptor blockers. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium.
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http://dx.doi.org/10.1002/cpt.2333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607432PMC
September 2021

Multi-Institutional Implementation of Clinical Decision Support for and Genotyping in Antihypertensive Management.

J Pers Med 2021 May 27;11(6). Epub 2021 May 27.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

(1) Background: Clinical decision support (CDS) is a vitally important adjunct to the implementation of pharmacogenomic-guided prescribing in clinical practice. A novel CDS was sought for the , , and genes to guide optimal selection of antihypertensive medications among the African American population cared for at multiple participating institutions in a clinical trial. (2) Methods: The CDS committee, made up of clinical content and CDS experts, developed a framework and contributed to the creation of the CDS using the following guiding principles: 1. medical algorithm consensus; 2. actionability; 3. context-sensitive triggers; 4. workflow integration; 5. feasibility; 6. interpretability; 7. portability; and 8. discrete reporting of lab results. (3) Results: Utilizing the principle of discrete patient laboratory and vital information, a novel CDS for , , and was created for use in a multi-institutional trial based on a medical algorithm consensus. The alerts are actionable and easily interpretable, clearly displaying the purpose and recommendations with pertinent laboratory results, vitals and links to ordersets with suggested antihypertensive dosages. Alerts were either triggered immediately once a provider starts to order relevant antihypertensive agents or strategically placed in workflow-appropriate general CDS sections in the electronic health record (EHR). Detailed implementation instructions were shared across institutions to achieve maximum portability. (4) Conclusions: Using sound principles, the created genetic algorithms were applied across multiple institutions. The framework outlined in this study should apply to other disease-gene and pharmacogenomic projects employing CDS.
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http://dx.doi.org/10.3390/jpm11060480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226809PMC
May 2021

Characterization of Reference Materials with an Association for Molecular Pathology Pharmacogenetics Working Group Tier 2 Status: CYP2C9, CYP2C19, VKORC1, CYP2C Cluster Variant, and GGCX: A GeT-RM Collaborative Project.

J Mol Diagn 2021 08 19;23(8):952-958. Epub 2021 May 19.

Division of Laboratory Systems, Centers for Disease Control and Prevention, Atlanta, Georgia. Electronic address:

Pharmacogenetic testing is increasingly available from clinical and research laboratories. However, only a limited number of quality control and other reference materials are currently available for many of the variants that are tested. The Association for Molecular Pathology Pharmacogenetic Work Group has published a series of papers recommending alleles for inclusion in clinical testing. Several of the alleles were not considered for tier 1 because of a lack of reference materials. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention-based Genetic Testing Reference Material (GeT-RM) program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 18 DNA samples derived from Coriell cell lines. DNA samples were distributed to five volunteer testing laboratories for genotyping using three commercially available and laboratory developed tests. Several tier 2 variants, including CYP2C9∗13, CYP2C19∗35, the CYP2C cluster variant (rs12777823), two variants in VKORC1 (rs61742245 and rs72547529) related to warfarin resistance, and two variants in GGCX (rs12714145 and rs11676382) related to clotting factor activation, were identified among these samples. These publicly available materials complement the pharmacogenetic reference materials previously characterized by the GeT-RM program and will support the quality assurance and quality control programs of clinical laboratories that perform pharmacogenetic testing.
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http://dx.doi.org/10.1016/j.jmoldx.2021.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491090PMC
August 2021

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

Genet Med 2021 07 29;23(7):1185-1191. Epub 2021 Mar 29.

Division of Genomic Medicine, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

Purpose: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.

Methods: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation.

Results: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression.

Conclusion: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.
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http://dx.doi.org/10.1038/s41436-021-01118-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263480PMC
July 2021

Expanding evidence leads to new pharmacogenomics payer coverage.

Genet Med 2021 05 24;23(5):830-832. Epub 2021 Feb 24.

Department of Biomedical Data Science and Medicine, Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1038/s41436-021-01117-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222707PMC
May 2021

Ending the pharmacogenomic gag rule: the imperative to report all results.

Pharmacogenomics 2021 03 24;22(4):191-193. Epub 2021 Feb 24.

Center for Bioethics, Indiana University, Indianapolis, IN 46202, USA.

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http://dx.doi.org/10.2217/pgs-2020-0172DOI Listing
March 2021

BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.

Am J Hum Genet 2020 12 23;107(6):1096-1112. Epub 2020 Nov 23.

Division of Clinical Genetics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA.

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820627PMC
December 2020

Characterization of Reference Materials for Spinal Muscular Atrophy Genetic Testing: A Genetic Testing Reference Materials Coordination Program Collaborative Project.

J Mol Diagn 2021 01 14;23(1):103-110. Epub 2020 Nov 14.

Informatics and Data Science Branch, Division of Laboratory Systems, CDC, Atlanta, Georgia. Electronic address:

Spinal muscular atrophy (SMA) is an autosomal recessive disorder predominately caused by bi-allelic loss of the SMN1 gene. Increased copies of SMN2, a low functioning nearly identical paralog, are associated with a less severe phenotype. SMA was recently recommended for inclusion in newborn screening. Clinical laboratories must accurately measure SMN1 and SMN2 copy number to identify SMA patients and carriers, and to identify individuals likely to benefit from therapeutic interventions. Having publicly available and appropriately characterized reference materials with various combinations of SMN1 and SMN2 copy number variants is critical to assure accurate SMA clinical testing. To address this need, the CDC-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and the Coriell Institute for Medical Research, has characterized 15 SMA reference materials derived from publicly available cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using three different methods. The characterized samples had zero to four copies of SMN1 and zero to five copies SMN2. The samples also contained clinically important allele combinations (eg, zero copies SMN1, three copies SMN2), and several had markers indicative of an SMA carrier. These and other reference materials characterized by the Genetic Testing Reference Materials Coordination Program are available from the Coriell Institute and are proposed to support the quality of clinical laboratory testing.
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http://dx.doi.org/10.1016/j.jmoldx.2020.10.011DOI Listing
January 2021

Identifying End Users' Preferences about Structuring Pharmacogenetic Test Orders in an Electronic Health Record System.

J Mol Diagn 2020 10;22(10):1264-1271

San Francisco VA Health Care System, San Francisco, California; Division of Hematology-Oncology, Department of Pediatrics University of California, San Francisco School of Medicine, San Francisco, California; Department of Medicine, and the Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California.

Pharmacogenetics (PGx) testing can be used for detecting genetic variations that may affect an individual's anticipated metabolism of, or response to, medications. Although several studies have focused on developing tools for delivering results from PGx testing, there is a relative dearth of information about how to design provider-friendly electronic order-entry systems for PGx. The U.S. Department of Veterans Affairs (VA) is preparing to implement a new electronic health records system. In this study, VA PGx test end users were surveyed about their preferences for how electronic test orders for PGx should be structured, including the nomenclature that should be used to search for and identify PGx-test orders, whether to offer single- versus multigene tests, and whether information about test methodology should be included in the order name. Responses were analyzed systematically to identify areas of agreement and disagreement with the survey options, and areas where respondents' opinions diverged. End users endorsed preferences for flexible ways to identify and order PGx tests and multigene panel tests; opinions on whether test methodology should be included in the test name were divergent. The results could be used for both informing the VA's new electronic health records implementation (including how PGx tests are searched for and ordered) and for providing insights for other health systems implementing PGx-testing programs.
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http://dx.doi.org/10.1016/j.jmoldx.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527867PMC
October 2020

EVEN-PLUS syndrome: A case report with novel variants in HSPA9 and evidence of HSPA9 gene dysfunction.

Am J Med Genet A 2020 11 1;182(11):2501-2507. Epub 2020 Sep 1.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

EVEN-PLUS syndrome is a rare condition characterized by its involvement of the Epiphyses, Vertebrae, Ears, and Nose, PLUS other associated findings. We report here the fifth case of EVEN-PLUS syndrome with novel variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in the HSPA9 gene identified through whole-exome sequencing. The patient is the first male known to be affected and presented with additional features not previously described with EVEN-PLUS syndrome. These features include agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. qPCR analysis provides supporting evidence for a nonsense-mediated decay mechanism for the HSPA9 truncating variant. In silico 3D modeling supports the pathogenicity of the c.955C > T (p.L319F) missense variant. The study presented here further describes the syndrome and broadens its mutational and phenotypic spectrum. Our study also lends support to HSPA9 variants as the underlying etiology of EVEN-PLUS syndrome and ultimately provides a better understanding of the molecular basis of the condition.
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http://dx.doi.org/10.1002/ajmg.a.61808DOI Listing
November 2020

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

Genet Med 2020 Oct;22(10):1730

Center for Applied Genomics & Precision Medicine, Duke University School of Medicine Durham, Durham, NC, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0911-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521989PMC
October 2020

Tracheal Aspirate as an Alternative Biologic Sample for Pharmacogenomics Testing in Mechanically Ventilated Pediatric Patients.

Clin Transl Sci 2021 03 25;14(2):497-501. Epub 2021 Jan 25.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Patients in the pediatric intensive care unit are exposed to multiple medications and are at high risk for adverse drug reactions. Pharmacogenomic (PGx) testing could help decrease their risk of adverse reactions. Although whole blood is preferred for PGx testing, blood volume in this population is often limited. However, for patients on mechanical ventilation, tracheal secretions are abundant, frequently suctioned, and discarded. Thus, the aim of this pilot study was to determine if tracheal aspirates could be used as a source of human genomic DNA for PGx testing. We successfully extracted DNA from tracheal secretions of all 23 patients in the study. The samples were successfully genotyped for 10 clinically actionable single nucleotide variants across 3 cytochrome P450 genes (CYP2D6, CYP2C19, and CYP3A5). Using DNA from whole blood samples in 11 of the patients, we confirmed the accuracy of the genotyping with 100% concordance. Therefore, our results support the use of tracheal aspirates from mechanically ventilated children as an adequate biospecimen for clinical genetic testing.
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http://dx.doi.org/10.1111/cts.12847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993287PMC
March 2021

PharmVar GeneFocus: CYP2C19.

Clin Pharmacol Ther 2021 02 22;109(2):352-366. Epub 2020 Jul 22.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. CYP2C19 genetic variation impacts the metabolism of many drugs and has been associated with both efficacy and safety issues for several commonly prescribed medications. This GeneFocus provides a comprehensive overview and summary of CYP2C19 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium (CPIC).
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http://dx.doi.org/10.1002/cpt.1973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769975PMC
February 2021

Recommendations for Clinical Warfarin Genotyping Allele Selection: A Report of the Association for Molecular Pathology and the College of American Pathologists.

J Mol Diagn 2020 07 4;22(7):847-859. Epub 2020 May 4.

The Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Departments of Pathology and Laboratory Medicine and Genetics, University of North Carolina, Chapel Hill, North Carolina.

The goal of the Association for Molecular Pathology (AMP) Clinical Practice Committee's AMP Pharmacogenomics (PGx) Working Group is to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variants, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal is to promote standardization of PGx gene/allele testing across clinical laboratories. These recommendations are not to be interpreted as prescriptive but to provide a reference guide. Of note, a separate article with recommendations for CYP2C9 allele selection was previously developed by the PGx Working Group that can be applied broadly to CYP2C9-related medications. The warfarin allele recommendations in this report incorporate the previous CYP2C9 allele recommendations and additional genes and alleles that are specific to warfarin testing.
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http://dx.doi.org/10.1016/j.jmoldx.2020.04.204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722527PMC
July 2020

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance.

Life (Basel) 2020 Mar 26;10(4). Epub 2020 Mar 26.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.
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http://dx.doi.org/10.3390/life10040032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235993PMC
March 2020

Influence of Uridine Diphosphate Glucuronosyltransferase Family 1 Member A1 and Solute Carrier Organic Anion Transporter Family 1 Member B1 Polymorphisms and Efavirenz on Bilirubin Disposition in Healthy Volunteers.

Drug Metab Dispos 2020 03 30;48(3):169-175. Epub 2019 Dec 30.

Department of Medicine, Division of Clinical Pharmacology (K.S.C., I.F.M., B.T.G., J.L., T.C.S., Z.D.), and Department of Medical and Molecular Genetics (E.B.M., V.M.P.), Indiana University School of Medicine, Indianapolis, Indiana

Chronic administration of efavirenz is associated with decreased serum bilirubin levels, probably through induction of We assessed the impact of efavirenz monotherapy and UGT1A1 phenotypes on total, conjugated, and unconjugated serum bilirubin levels in healthy volunteers. Healthy volunteers were enrolled into a clinical study designed to address efavirenz pharmacokinetics, drug interactions, and pharmacogenetics. Volunteers received multiple oral doses (600 mg/day for 17 days) of efavirenz. Serum bilirubin levels were obtained at study entry and 1 week after completion of the study. DNA genotyping was performed for [ (C>T), (G>A), (TA), (TA), and (TA)] and for [ (521T>C) and (388A>G] variants. Diplotype predicted phenotypes were classified as normal, intermediate, and slow metabolizers. Compared with bilirubin levels at screening, treatment with efavirenz significantly reduced total, conjugated, and unconjugated bilirubin. After stratification by UGT1A1 phenotypes, there was a significant decrease in total bilirubin among all phenotypes, conjugated bilirubin among intermediate metabolizers, and unconjugated bilirubin among normal and intermediate metabolizers. The data also show that genotype predicts serum bilirubin levels at baseline, but this relationship is lost after efavirenz treatment. genotypes did not predict bilirubin levels at baseline or after efavirenz treatment. Our data suggest that efavirenz may alter bilirubin disposition mainly through induction of UGT1A1 metabolism and efflux through multidrug resistance-associated protein 2. SIGNIFICANCE STATEMENT: Efavirenz likely alters the pharmacokinetics of coadministered drugs, potentially causing lack of efficacy or increased adverse effects, as well as the disposition of endogenous compounds relevant in homeostasis through upregulation of UGT1A1 and multidrug resistance-associated protein 2. Measurement of unconjugated and conjugated bilirubin during new drug development may provide mechanistic understanding regarding enzyme and transporters modulated by the new drug.
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http://dx.doi.org/10.1124/dmd.119.089052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011111PMC
March 2020

PharmVar and the Landscape of Pharmacogenetic Resources.

Clin Pharmacol Ther 2020 01 23;107(1):43-46. Epub 2019 Nov 23.

Department of Biomedical Data Science, Stanford University, Stanford, California, USA.

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http://dx.doi.org/10.1002/cpt.1654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925620PMC
January 2020

An unusual cause for Coffin-Lowry syndrome: Three brothers with a novel microduplication in RPS6KA3.

Am J Med Genet A 2019 12 12;179(12):2357-2364. Epub 2019 Sep 12.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.

Coffin-Lowry syndrome (CLS) is a rare X-linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high-resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT-PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss-of-function mechanism. PCR analysis of the patients' cDNA detected a band greater than expected for an exon 4-10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next-generation sequencing and high-resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases.
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http://dx.doi.org/10.1002/ajmg.a.61353DOI Listing
December 2019

Characterization of Reference Materials for Genetic Testing of CYP2D6 Alleles: A GeT-RM Collaborative Project.

J Mol Diagn 2019 11 9;21(6):1034-1052. Epub 2019 Aug 9.

Informatics and Data Science Branch, Division of Laboratory Systems, Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, Georgia. Electronic address:

Pharmacogenetic testing increasingly is available from clinical and research laboratories. However, only a limited number of quality control and other reference materials currently are available for the complex rearrangements and rare variants that occur in the CYP2D6 gene. To address this need, the Division of Laboratory Systems, CDC-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Cell Repositories (Camden, NJ), has characterized 179 DNA samples derived from Coriell cell lines. Testing included the recharacterization of 137 genomic DNAs that were genotyped in previous Genetic Testing Reference Material Coordination Program studies and 42 additional samples that had not been characterized previously. DNA samples were distributed to volunteer testing laboratories for genotyping using a variety of commercially available and laboratory-developed tests. These publicly available samples will support the quality-assurance and quality-control programs of clinical laboratories performing CYP2D6 testing.
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http://dx.doi.org/10.1016/j.jmoldx.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854474PMC
November 2019

Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists.

J Mol Diagn 2019 09 8;21(5):746-755. Epub 2019 May 8.

The Pharmacogenomics (PGx) Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Department of Pathology and Laboratory Medicine and Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.

The goals of the Association for Molecular Pathology Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee are to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9 testing. The Working Group considered the functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. Our goal is to promote standardization of testing PGx genes and alleles across clinical laboratories. These recommendations are not to be interpreted as restrictive but to provide a reference guide. The current document will focus on CYP2C9 testing that can be applied to all CYP2C9-related medications. A separate recommendation on warfarin PGx testing is being developed to include recommendations on CYP2C9 alleles and additional warfarin sensitivity-associated genes and alleles.
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http://dx.doi.org/10.1016/j.jmoldx.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057225PMC
September 2019

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

Genet Med 2019 10 21;21(10):2255-2263. Epub 2019 Mar 21.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.

Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.

Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.

Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.

Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
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http://dx.doi.org/10.1038/s41436-019-0484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754805PMC
October 2019

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology.

J Mol Diagn 2019 05 20;21(3):491-502. Epub 2019 Feb 20.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana.

The Clinical Laboratory Improvement Amendments of 1988 require that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a Clinical Laboratory Improvement Amendments-accredited laboratory. Because no known reference materials were available, existing DNA samples were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other Clinical Laboratory Improvement Amendments-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.
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http://dx.doi.org/10.1016/j.jmoldx.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504676PMC
May 2019

Drug-gene and drug-drug interactions associated with tramadol and codeine therapy in the INGENIOUS trial.

Pharmacogenomics 2019 04 20;20(6):397-408. Epub 2019 Feb 20.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions. This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126). Within 60 days of receiving tramadol or codeine, clinicians more frequently prescribed an alternative opioid in ultrarapid and poor metabolizers (odds ratio: 19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94). Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.
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http://dx.doi.org/10.2217/pgs-2018-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562829PMC
April 2019

Response to Gammal et al.

Genet Med 2019 08 12;21(8):1888-1889. Epub 2019 Jan 12.

Pharmacogenomics Analysis Laboratory, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.

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http://dx.doi.org/10.1038/s41436-018-0422-9DOI Listing
August 2019

Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy.

Pharmacogenet Genomics 2019 01;29(1):18-22

Departments of Medicine.

Hypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy.
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http://dx.doi.org/10.1097/FPC.0000000000000361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358457PMC
January 2019

Report of Confirmation of the rs7853758 and rs885004 Haplotype in SLC28A3.

Genet Test Mol Biomarkers 2018 Nov 23;22(11):652-655. Epub 2018 Oct 23.

1 Department of Medical and Molecular Genetics and Indiana University School of Medicine , Indianapolis, Indiana.

Aims: To validate a laboratory-developed test for the nucleoside transporter, SLC28A3, which has been associated with an increased risk of anthracycline-induced cardiomyopathy.

Methods: We used Taqman allele discrimination to test for two variants of the SLC28A3 gene: rs7853758 (c.1381C>T) and rs885004 (c.862-360C>T).

Results: During the validation process, we noted that several DNA samples obtained from the Coriell Cell Repository (Camden, NJ) were positive for both the c.1381 C > T and c.862-360C>T variants and another variant allele for either c.1381 C > T or c.862-360C>T (e.g., c.1381C>T homozygous/c.862-360C>T heterozygous, c.1381C>T homozygous/c.862-360C>T homozygous). We used de-identified DNA samples from trios of family members (mother, father, and child) to establish that the c.1381 C > T and c.862-360C>T variant alleles could be inherited in cis on the same chromosome.

Conclusions: Samples containing three variant alleles suggest that the c.1381 C > T and c.862-360C>T are in cis on the chromosome in some individuals and may have implications when calculating anthracycline-induced cardiomyopathy risk. In this study, we confirm a novel haplotype of SLC28A3 using familial studies.
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http://dx.doi.org/10.1089/gtmb.2018.0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249667PMC
November 2018
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