Next-generation sequencing (NGS) represents an efficient and reliable method to evaluate the contribution of both common and rare polymorphisms to the genetic variation in pharmacological research. Furthermore, recent studies that analysed NGS data on pharmacogenes indicated 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, Ingelman-Sundberg and Lauschke, 2015; Kozyra, Ingelman-Sundberg and Lauschke, 2017).
While sequencing technology has identified many rare and very rare variants, more comprehensive subsequent research must be done 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). Regardless, NGS has the potential to enable more precise prediction of drug phenotypes in patients and allow the implementation of genotype-based dose adjustments in clinical settings in the future (Schwarz, Gulilat and Kim, 2019).
Dr Nina Fajs
Clinical Scientist, Edinburgh Genetics
