Among the most researched such genes are the ones belonging to the CYP gene superfamily, which is thought to cause up to 60% of drug-induced toxicity (Maggo, Savage and Kennedy, 2016). Recent studies that analysed NGS data on pharmacogenes show that the majority of all variants found in coding regions were rare and very rare (93% with minor allele frequency [MAF] <1% and 83% with MAF < 0.01% respectively), with 30-40% of the functional variability contributed to these variants (Fujikura et al., 2015; Kozyra et al., 2017). While sequencing technology has identified many rare and very rare variants, more comprehensive research is ongoing to assess their functional and clinical significance and further clarify their effects and relevance.
The current challenges for clinical use of NGS-based results include a high degree of homology among the pharmacogenes (leading to misalignment of sequence reads to the referent genome), the existence of highly polymorphic genes with complex structural variation (e.g. some CYP and HLA family genes) and limited prediction capability for the novel haplotype structures (Russell and Schwarz, 2020).
Combined with extensive research, egSEQ library preparation and sequencing solutions provide cost-effective solutions to enable more precise prediction of drug phenotypes in patients and allow the implementation of genotype-based dose adjustments in clinical settings.
Fujikura, K., Ingelman-Sundberg, M., & Lauschke, V. M. (2015). Genetic variation in the human cytochrome P450 supergene family. Pharmacogenetics and genomics, 25(12), 584-594.
Kozyra, M., Ingelman-Sundberg, M., & Lauschke, V. M. (2017). Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response. Genetics in Medicine, 19(1), 20-29.
Russell, L. E., & Schwarz, U. I. (2020). Variant discovery using next-generation sequencing and its future role in pharmacogenetics. Pharmacogenomics, 21(7), 471-486.