CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis: A GeT-RM Collaborative Project.
Document Type
Article
Publication Date
4-1-2022
Identifier
DOI: 10.1016/j.jmoldx.2021.12.011
Abstract
Pharmacogenetic tests typically target selected sequence variants to identify haplotypes that are often defined by star (∗) allele nomenclature. Due to their design, these targeted genotyping assays are unable to detect novel variants that may change the function of the gene product and thereby affect phenotype prediction and patient care. In the current study, 137 DNA samples that were previously characterized by the Genetic Testing Reference Material (GeT-RM) program using a variety of targeted genotyping methods were recharacterized using targeted and whole genome sequencing analysis. Sequence data were analyzed using three genotype calling tools to identify star allele diplotypes for CYP2C8, CYP2C9, and CYP2C19. The genotype calls from next-generation sequencing (NGS) correlated well to those previously reported, except when novel alleles were present in a sample. Six novel alleles and 38 novel suballeles were identified in the three genes due to identification of variants not covered by targeted genotyping assays. In addition, several ambiguous genotype calls from a previous study were resolved using the NGS and/or long-read NGS data. Diplotype calls were mostly consistent between the calling algorithms, although several discrepancies were noted. This study highlights the utility of NGS for pharmacogenetic testing and demonstrates that there are many novel alleles that are yet to be discovered, even in highly characterized genes such as CYP2C9 and CYP2C19.
Journal Title
The Journal of molecular diagnostics : JMD
Volume
24
Issue
4
First Page
337
Last Page
350
MeSH Keywords
Alleles; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C9; Genetic Testing; Genotype; Haplotypes; High-Throughput Nucleotide Sequencing; Humans
Keywords
Alleles; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C9; Genetic Testing; Genotype; Haplotypes; High-Throughput Nucleotide Sequencing; Humans
Recommended Citation
Gaedigk A, Boone EC, Scherer SE, et al. CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis: A GeT-RM Collaborative Project. J Mol Diagn. 2022;24(4):337-350. doi:10.1016/j.jmoldx.2021.12.011
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