TY - JOUR
T1 - Targeted Genotyping in Clinical Pharmacogenomics
T2 - What Is Missing?
AU - Lopes, Jaime L.
AU - Harris, Kimberley
AU - Karow, Mary Beth
AU - Peterson, Sandra E.
AU - Kluge, Michelle L.
AU - Kotzer, Katrina E.
AU - Lopes, Guilherme S.
AU - Larson, Nicholas B.
AU - Bielinski, Suzette J.
AU - Scherer, Steven E.
AU - Wang, Liewei
AU - Weinshilboum, Richard M.
AU - Black, John L.
AU - Moyer, Ann M.
N1 - Publisher Copyright:
© 2022 Association for Molecular Pathology and American Society for Investigative Pathology
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jmoldx.2021.11.008
DO - 10.1016/j.jmoldx.2021.11.008
M3 - Article
C2 - 35041929
AN - SCOPUS:85125544340
SN - 1525-1578
VL - 24
SP - 253
EP - 261
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 3
ER -