Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience

Lee, Elizabeth M.J.; Xu, Karen L.; Mosbrook, Emma; Links, Amanda; Adams, David R.; Flynn, Elise D.; Valkanas, Elise; Tifft, Cynthia J.; Boerkoel, Cornelius F.; Gahl, William A.; Sincan, Murat

doi:10.1038/gim.2016.47

Cited by 16 publications

(18 citation statements)

References 20 publications

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“…A recent study from the NIH Undiagnosed Diseases Program (Lee et al. ) also established that PGx results were informative for guiding therapy in their cohort of 308 families. Lee and colleagues evaluated single nucleotide changes that have been reported to impact drug efficacy based on Pharmacogenomics Knowledgebase (PharmGKB).…”

Section: Discussionmentioning

confidence: 99%

“…If we were to pursue PGx testing based on individual medication usage and according to the current actionable genedrug pairs for drug metabolizing genes used at Mayo Clinic (Cook et al 2015), 43 patients would be tested for CYP3A4/5, 35 for CYP2C19, 22 for CYP2D6, 8 for CYP1A2 (MIM:124060), and 9 for CYP2C9. A recent study from the NIH Undiagnosed Diseases Program (Lee et al 2016) also established that PGx results were informative for guiding therapy in their cohort of 308 families. Lee and colleagues evaluated single nucleotide changes that have been reported to impact drug efficacy based on Pharmacogenomics Knowledgebase (PharmGKB).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients

Cousin

Matey

Blackburn

et al. 2017

Molec Gen & Gen Med

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BackgroundWe characterized the pharmacogenomics (PGx) results received by diagnostic odyssey patients as secondary findings during clinical whole exome sequencing (WES) testing as a part of their care in Mayo Clinic's Individualized Medicine Clinic to determine the potential benefits and limitations to this cohort.Methods WES results on 94 patients included a subset of PGx variants in CYP2C19,CYP2C9, and VKORC1 if identified in the patient. Demographic, phenotypic, and medication usage information was abstracted from patient medical data. A pharmacist interpreted the PGx results in the context of the patients’ current medication use and made therapeutic recommendations.ResultsThe majority was young with a median age of 10 years old, had neurological involvement in the disease presentation (71%), and was currently taking medications (90%). Of the 94 PGx‐evaluated patients, 91% had at least one variant allele reported and 20% had potential immediate implications on current medication use.ConclusionDue to the disease complexity and medication needs of diagnostic odyssey patients, there may be immediate benefit obtained from early life PGx testing for many and most will likely find benefit in the future. These results require conscientious interpretation and management to be actionable for all prescribing physicians throughout the lifetime of the patient.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients

Cousin

Matey

Blackburn

et al. 2017

Molec Gen & Gen Med

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“…Over 80% of patients who elected to receive pharmacogenomic findings had at least one actionable result. An investigation of ∼1,100 individuals utilizing data obtained from WES and SNP genotyping found that all individuals had an incidental pharmacogenomic finding; however, the majority of the findings were not clinically significant . Our analysis focused only on gene–drug pairs with evidence‐based guidelines for clinical implementation.…”

Section: Discussionmentioning

confidence: 99%

Patient Decisions to Receive Secondary Pharmacogenomic Findings and Development of a Multidisciplinary Practice Model to Integrate Results Into Patient Care

Hicks

Shealy

Schreiber

et al. 2017

Clinical Translational Sci

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Whole exome sequencing (WES) has the potential of identifying secondary findings that are predictive of poor pharmacotherapy outcomes. The purpose of this study was to investigate patients’ wishes regarding the reporting of secondary pharmacogenomic findings. WES results (n = 106 patients) were retrospectively reviewed to determine the number of patients electing to receive secondary pharmacogenomic results. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The percent of patients with a predicted phenotype associated with a gene‐based CPIC dosing recommendation was determined. Ninety‐nine patients (93.4%) elected to receive secondary pharmacogenomic findings. For each gene–drug pair analyzed, the number of patients with an actionable phenotype ranged from two (2%) to 43 patients (43.4%). Combining all gene–drug pairs, 84 unique patients (84.8%) had an actionable phenotype. A prospective multidisciplinary practice model was developed for integrating secondary pharmacogenomic findings into clinical practice. Our model highlights a unique collaboration between physician‐geneticists, pharmacists, and genetic counselors.

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“…Nineteen PharmGKB 1A/1B variants or combinations of variants from the list used at the time of the work were identified in SNP chip sequence data, and 21 PharmGKB 1A/1B variants or combinations of variants were identified in the exome-sequence data using the TruSeq kit (Illumina). Only nine participants had pharmacogenetic IFs/SFs associated with altered efficacy of a prescribed medication, demonstrating that some pharmacogenetic IFs could be potentially useful for guiding therapy, and could be worth reporting [37]. However, another study that interviewed 159 Mayo Clinic clinicians revealed that half of them were uncomfortable with the inclusion of pharmacogenomic data in primary care.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, our results were limited by the non-determination of all CYP2D6 variants. Another Mayo Clinic study outlined the necessity of using a custom genotyping method to determine all CYP2D6 variants or combinations of variants [37]. If we do not focus on the extreme alleles, 415/700 different patients had at least one listed variant or combination of variants from the PharmGKB 1A category within the CYP2C19 and CYP2C9 gene, relevant to toxicity or variability of pharmacokinetics or pharmacodynamics of different medications (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests

et al. 2019

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With exome/genome sequencing (ES/GS) integrated into the practice of medicine, there is some potential for reporting incidental/secondary findings (IFs/SFs). The issue of IFs/SFs has been studied extensively over the last 4 years. In order to evaluate their implications in care organisation, we retrospectively evaluated, in a cohort of 700 consecutive probands, the frequency and burden of introducing the search for variants in a maximum list of 244 medically actionable genes (genes that predispose carriers to a preventable or treatable disease in childhood/adulthood and genes for genetic counselling issues). We also focused on the 59 PharmGKB class IA/IB pharmacogenetic variants. We also compared the results in different gene lists. We identified variants (likely) affecting protein function in genes for care in 26 cases (3.7%) and heterozygous variants in genes for genetic counselling in 29 cases (3.8%). Mean time for the 700 patients was about 6.3 min/patient for medically actionable genes and 1.3 min/patient for genes for genetic counselling, and a mean time of 37 min/patients for the reinterpreted variants. These results would lead to all 700 pre-test counselling sessions being longer, to 55 post-test genetic consultations and to 27 secondary specialised medical evaluations. ES also detected 42/59 pharmacogenetic variants or combinations of variants in the majority of cases. An extremely low metabolizer status in genes relevant for neurodevelopmental disorders (CYP2C9 and CYP2C19) was found in 57/700 cases. This study provides information regarding the need to anticipate the implementation of genomic medicine, notably the work overload at various steps of the process.

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Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience

Cited by 16 publications

References 20 publications

Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients

Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients

Patient Decisions to Receive Secondary Pharmacogenomic Findings and Development of a Multidisciplinary Practice Model to Integrate Results Into Patient Care

Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests

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