Targeted Genotyping in Clinical Pharmacogenomics: What Is Missing?

TitleTargeted Genotyping in Clinical Pharmacogenomics: What Is Missing?
Publication TypeJournal Article
Year of Publication2022
AuthorsLopes, JL, Harris, K, Karow, MBeth, Peterson, SE, Kluge, ML, Kotzer, KE, Lopes, GS, Larson, NB, Bielinski, SJ, Scherer, SE, Wang, L, Weinshilboum, RM, Black, JL, Moyer, AM
JournalJ Mol Diagn
Date Published2022 Mar
KeywordsAlleles, Cytochrome P-450 CYP2D6, Genotype, Humans, Liver-Specific Organic Anion Transporter 1, Pharmacogenetics, Pharmacogenomic Testing, Vitamin K Epoxide Reductases

Clinical pharmacogenomic testing typically uses targeted genotyping, which only detects variants included in the test design and may vary among laboratories. To evaluate the potential patient impact of genotyping compared with sequencing, which can detect common and rare variants, an in silico targeted genotyping panel was developed based on the variants most commonly included in clinical tests and applied to a cohort of 10,030 participants who underwent sequencing for CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DPYD, SLCO1B1, TPMT, UGT1A1, and VKORC1. The results of in silico targeted genotyping were compared with the clinically reported sequencing results. Of the 10,030 participants, 2780 (28%) had at least one potentially clinically relevant variant/allele identified by sequencing that would not have been detected in a standard targeted genotyping panel. The genes with the largest number of participants with variants only detected by sequencing were SLCO1B1, DPYD, and CYP2D6, which affected 13%, 6.3%, and 3.5% of participants, respectively. DPYD (112 variants) and CYP2D6 (103 variants) had the largest number of unique variants detected only by sequencing. Although targeted genotyping detects most clinically significant pharmacogenomic variants, sequencing-based approaches are necessary to detect rare variants that collectively affect many patients. However, efforts to establish pharmacogenomic variant classification systems and nomenclature to accommodate rare variants will be required to adopt sequencing-based pharmacogenomics.

Alternate JournalJ Mol Diagn
PubMed ID35041929
PubMed Central IDPMC8961466
Grant ListU19 GM061388 / GM / NIGMS NIH HHS / United States
R01 AG034676 / AG / NIA NIH HHS / United States
R01 GM028157 / GM / NIGMS NIH HHS / United States
T32 HL007111 / HL / NHLBI NIH HHS / United States
R33 AG058738 / AG / NIA NIH HHS / United States
U01 HG005137 / HG / NHGRI NIH HHS / United States
U01 HG006379 / HG / NHGRI NIH HHS / United States
R01 GM125633 / GM / NIGMS NIH HHS / United States