Targeted Genotyping in Clinical Pharmacogenomics: What Is Missing?

Area of Science:

• Pharmacogenomics
• Genetics
• Clinical Diagnostics

Background:

• Clinical pharmacogenomic testing commonly uses targeted genotyping.
• Targeted genotyping panels may miss clinically relevant variants.
• Sequencing offers comprehensive detection of common and rare variants.

Purpose of the Study:

• To compare the diagnostic yield of in silico targeted genotyping with comprehensive sequencing.
• To evaluate the patient impact of variants missed by targeted genotyping.
• To assess the utility of sequencing for pharmacogenomic variant detection.

Main Methods:

• An in silico targeted genotyping panel was designed based on common clinical variants.
• The panel was applied to 10,030 participants with existing sequencing data.
• Results were compared between in silico genotyping and reported sequencing findings for genes including CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DPYD, SLCO1B1, TPMT, UGT1A1, and VKORC1.

Main Results:

• Sequencing identified potentially clinically relevant variants in 28% (2780/10,030) of participants missed by targeted genotyping.
• SLCO1B1 (13%), DPYD (6.3%), and CYP2D6 (3.5%) had the highest proportion of variants uniquely detected by sequencing.
• DPYD and CYP2D6 exhibited the largest number of unique variants exclusively identified through sequencing.

Conclusions:

• Targeted genotyping captures most significant pharmacogenomic variants but misses rare alleles.
• Sequencing-based approaches are crucial for comprehensive pharmacogenomic profiling, detecting variants that collectively impact many patients.
• Standardization of variant classification and nomenclature is needed for widespread adoption of sequencing in pharmacogenomics.