ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation. 2022

Seung-Been Lee, and Jong-Yeon Shin, and Nak-Jung Kwon, and Changhoon Kim, and Jeong-Sun Seo
Macrogen Inc, Seoul, Republic of Korea.

The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug therapy. Targeted sequencing has recently become a common methodology for large-scale studies of genetic variation thanks to its favorable balance between low cost, high throughput, and deep coverage. Here, we present ClinPharmSeq, a targeted sequencing panel of 59 genes with associations to pharmacogenetic (PGx) phenotypes, as a platform to explore the relationship between drug response and genetic variation, both common and rare. For validation, we sequenced DNA from 64 ethnically diverse Coriell samples with ClinPharmSeq to call star alleles (haplotype patterns) in 27 genes using the bioinformatics tool PyPGx. These reference samples were extensively characterized by multiple laboratories using PGx testing assays and, more recently, whole genome sequencing. We found that ClinPharmSeq can consistently generate deep-coverage data (mean = 274x) with high uniformity (30x or above = 94.8%). Our genotype analysis identified a total of 185 unique star alleles from sequencing data, and showed that diplotype calls from ClinPharmSeq are highly concordant with that from previous publications (97.6%) and whole genome sequencing (97.9%). Notably, all 19 star alleles with complex structural variation including gene deletions, duplications, and hybrids were recalled with 100% accuracy. Altogether, these results demonstrate that the ClinPharmSeq platform offers a feasible path for broad implementation of PGx testing and optimization of individual drug treatments.

UI MeSH Term Description Entries
D010597 Pharmacogenetics A branch of genetics which deals with the genetic variability in individual responses to drugs and drug metabolism (BIOTRANSFORMATION). Pharmacogenomics
D005838 Genotype The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS. Genogroup,Genogroups,Genotypes
D006239 Haplotypes The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX. Haplotype
D000073336 Whole Genome Sequencing Techniques to determine the entire sequence of the GENOME of an organism or individual. Complete Genome Sequencing,Genome Sequencing, Complete,Genome Sequencing, Whole,Sequencing, Complete Genome,Sequencing, Whole Genome
D000483 Alleles Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product. Allelomorphs,Allele,Allelomorph
D059014 High-Throughput Nucleotide Sequencing Techniques of nucleotide sequence analysis that increase the range, complexity, sensitivity, and accuracy of results by greatly increasing the scale of operations and thus the number of nucleotides, and the number of copies of each nucleotide sequenced. The sequencing may be done by analysis of the synthesis or ligation products, hybridization to preexisting sequences, etc. High-Throughput Sequencing,Illumina Sequencing,Ion Proton Sequencing,Ion Torrent Sequencing,Next-Generation Sequencing,Deep Sequencing,High-Throughput DNA Sequencing,High-Throughput RNA Sequencing,Massively-Parallel Sequencing,Pyrosequencing,DNA Sequencing, High-Throughput,High Throughput DNA Sequencing,High Throughput Nucleotide Sequencing,High Throughput RNA Sequencing,High Throughput Sequencing,Massively Parallel Sequencing,Next Generation Sequencing,Nucleotide Sequencing, High-Throughput,RNA Sequencing, High-Throughput,Sequencing, Deep,Sequencing, High-Throughput,Sequencing, High-Throughput DNA,Sequencing, High-Throughput Nucleotide,Sequencing, High-Throughput RNA,Sequencing, Illumina,Sequencing, Ion Proton,Sequencing, Ion Torrent,Sequencing, Massively-Parallel,Sequencing, Next-Generation

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