The Use of Next-Generation Sequencing in Pharmacogenomics

Enko, Dietmar; Michaelis, Simon; Schneider, Christopher; Schaflinger, Erich; Baranyi, Andreas; Schnedl, W.; Müller, Daniel J.

doi:10.7754/clin.lab.2023.230103

Cited by 3 publications

(4 citation statements)

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“…The guidelines for PGx testing and phenoconversion are supported by rigorous evidence and processes; however, updates to these guidelines do not keep pace with the emergence of new evidence [7,8,14,[18][19][20]. New variants can be discovered with next-generation sequencing (NGS) but need to be validated in other studies using comparable technology and methods [21]. For instance, one haplotype recently described involves two loci between CYP2C18 and CYP2C19 that affects selective serotonin reuptake inhibitor (SSRI) metabolism -called the "CYP2C haplotype" [22].…”

Section: Introductionmentioning

confidence: 99%

“…Most clinical PGx assays and commercial assays (targeted single-nucleotide polymorphism [SNP] assays) likely only test haplotypes described in guidelines [25][26][27] and cannot accurately assign CYP2D6 CNVs to an allele [21]. NGS provides the opportunity to interrogate CYP2D6 allele-specific CNVs and novel variations like the CYP2C haplotype.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients

Patel,

Morris,

Torres

et al. 2024

Mol Psychiatry

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Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients

Patel,

Morris,

Torres

et al. 2024

Mol Psychiatry

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“…Next Generation Sequencing (NGS) technologies have accelerated the advances in all biological and medical research in the past two decades [10][11][12][13]. RNA-sequencing…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Intron in US10/US11/US12 of HSV-1 Strain 17

Chang,

Hao,

Qiu

et al. 2023

Viruses

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Herpes Simplex Virus type 1 (HSV-1) infects humans and causes a variety of clinical manifestations. Many HSV-1 genomes have been sequenced with high-throughput sequencing technologies and the annotation of these genome sequences heavily relies on the known genes in reference strains. Consequently, the accuracy of reference strain annotation is critical for future research and treatment of HSV-1 infection. In this study, we analyzed RNA-Seq data of HSV-1 from NCBI databases and discovered a novel intron in the overlapping coding sequence (CDS) of US10 and US11, and the 3′ UTR of US12 in strain 17, a commonly used HSV-1 reference strain. To comprehensively understand the shared US10/US11/US12 intron structure, we used US11 as a representative and surveyed all US11 gene sequences from the NCBI nt/nr database. A total of 193 high-quality US11 sequences were obtained, of which 186 sequences have a domain of uninterrupted tandemly repeated RXP (Arg-X-Pro) in the C-terminus half of the protein. In total, 97 of the 186 sequences encode US11 protein with the same length of the mature US11 in strain 17:26 of them have the same structure of US11 and can be spliced as in strain 17; 71 of them have transcripts that are the same as mature US11 mRNA in strain 17. In total, 76 US11 gene sequences have either canonical or known noncanonical intron border sequences and may be spliced like strain 17 and obtain mature US11 CDS with the same length. If not spliced, they will have extra RXP repeats. A tandemly repeated RXP domain was proposed to be essential for US11 to bind with RNA and other host factors. US10 protein sequences from the same strains have also been studied. The results of this study show that even a frequently used reference organism may have errors in widely used databases. This study provides accurate annotation of the US10, US11, and US12 gene structure, which will build a more solid foundation to study expression regulation of the function of these genes.

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“…The guidelines for PGx testing and phenoconversion are supported by rigorous evidence and processes; however, updates to these guidelines do not keep pace with the emergence of new evidence. New variants can be discovered with next-generation sequencing (NGS), but need to be validated in other studies using comparable technology and methods [18] . For instance, one haplotype recently described involves two loci between CYP2C18 and CYP2C19 that affects selective serotonin reuptake inhibitor (SSRI) metabolism -called the " CYP2C haplotype" [19] .…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic Insights in Psychiatric Care: Uncovering Novel Actionability, Allele-Specific CYP2D6 Copy Number Variation, and Phenoconversion in 15,000 Patients

Stanton,

Patel,

Morris

et al. 2023

Preprint

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Pharmacogenomic testing has emerged as an aid in clinical decision-making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of patients. Of 4,114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of actionability from genetic findings and/or phenoconversion, and genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

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The Use of Next-Generation Sequencing in Pharmacogenomics

Cited by 3 publications

References 0 publications

Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients

Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients

Discovery of a Novel Intron in US10/US11/US12 of HSV-1 Strain 17

Pharmacogenomic Insights in Psychiatric Care: Uncovering Novel Actionability, Allele-Specific CYP2D6 Copy Number Variation, and Phenoconversion in 15,000 Patients

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