Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C9 and HLA-B Genotype and Phenytoin Dosing

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large inter-patient variability partly due to genetic variations in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: www.pharmgkb.org)

Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153095/1/cts12692_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153095/2/cts12692-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153095/3/cts12692.pd

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects\u27 phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs

Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by medication exposure. Regulatory agencies worldwide warn against the use of certain medications in persons with G6PD deficiency, but in many cases, this information is conflicting, and the clinical evidence is sparse. This guideline provides information on using G6PD genotype as part of the diagnosis of G6PD deficiency and classifies medications that have been previously implicated as unsafe in individuals with G6PD deficiency by one or more sources. We classify these medications as high, medium, or low to no risk based on a systematic review of the published evidence of the gene-drug associations and regulatory warnings. In patients with G6PD deficiency, high-risk medications should be avoided, medium-risk medications should be used with caution, and low-to-no risk medications can be used with standard precautions, without regard to G6PD phenotype. This new document replaces the prior Clinical Pharmacogenetics Implementation Consortium guideline for rasburicase therapy in the context of G6PD genotype (updates at: www.cpicpgx.org)

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting

This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward

Digital Storytelling Project on Library Anxiety

The Digital Storytelling Project on Library Anxiety began as a project in a service learning course offered by the Film and Media Studies Department at the University of Kansas (KU). In spring 2015, three undergraduate students enrolled in the course collaborated with KU Libraries to create an interactive, digital game addressing experiences of library anxiety among undergraduate students that could be integrated into first-year-experience courses offered by the university. The original student team created the game’s branching pathways within Twine, wrote the game text, and drafted a small number of animated GIFs that established the tone for the game. In spring 2016, after receiving funding to support production of the game’s missing elements, KU Libraries contracted one of the student team members to create the remaining illustrations and ensure their integration into the Twine file. Type-specific handouts were created to supplement the game, which was integrated into KU’s University 101 courses beginning in fall 2016. Additional authorship information is located in the Read Me.The Digital Storytelling Project on Library Anxiety is a student-designed, interactive game intended to introduce first-year students to KU Libraries’ resources and services. It adopts a fun yet informative tone to lower library anxiety among incoming freshmen and illustrate the benefits of library use.The project was funded by KU Libraries' Center for Undergraduate Initiatives & Engagement and the Libraries Research Fund

An investigation into the potential clinical use of APOE testing in the population of athletes at risk for traumatic brain injury: A survey of athletes

Routine use of APOE genotyping, with its association to an increased risk of late-onset Alzheimer’s disease (LOAD), is controversial and has been discouraged by professional organizations, in part because predictive information on LOAD is not clinically useful (ASHG, 1995; NSGC, 2012). Recent studies indicating that APOE genotype is also associated with the risk of a poor recovery from traumatic brain injury (TBI) suggest that APOE genotyping may have clinical value for athletes, either in determining the level of risk associated with participation in high TBI incidence sports, or in personalizing treatment of TBI and decision making around return-to-play. This study examined the interest of NCAA student-athletes in APOE genotyping, the barriers to testing, and their perception of the potential ramifications of finding out their APOE genotype. A survey of 843 Division I, II and III NCAA athletes indicated widespread interest in APOE genotyping. The vast majority (92.5%, n=780) were willing to test if it was required by the school, and most indicated that they would test if it were voluntary (75.9%, n=639). Student –athletes seemed largely unconcerned with potential ramifications of testing, and indicated that they would tell their coaches (75.7%, n=638), their parents (86.1%, n=725) and their doctors (86.0%, n=725). Students suggested that they did not expect testing to impact their behavior (59.4%, n=500) or their style of play (67.4%, n=568). Students were interested in learning more about their risk for LOAD and few indicated this made them less likely to test (12.4%, n=104). Despite this apparent lack of concern, most students indicated that they would prefer having the option of genetic counseling (51.5%, n=434) and the majority expressed an interest in meeting with a genetic counselor to discuss their results (62.5%, n=527). Study findings suggest a need to consider the appropriate use of APOE genotyping in this setting, and the role that genetic counselors might play in ensuring that athletes are adequately informed of all potential harms and benefits

Standardization can accelerate the adoption of pharmacogenomics: current status and the path forward

Successfully implementing pharmacogenomics into routine clinical practice requires an efficient process to order genetic tests and report the results to clinicians and patients. Lack of standardized approaches and terminology in clinical laboratory processes, ordering of the test and reporting of test results all impede this workflow. Expert groups such as the Association for Molecular Pathology and the Clinical Pharmacogenetics Implementation Consortium have published recommendations for standardizing laboratory genetic testing, reporting and terminology. Other resources such as PharmGKB, ClinVar, ClinGen and PharmVar have established databases of nomenclature for pharmacogenetic alleles and variants. Opportunities remain to develop new standards and further disseminate existing standards which will accelerate the implementation of pharmacogenomics