Importance of adaptive sampling in nanopore long-read sequencing in pharmacogenetics

Abstract

Pharmacogenetics is a major driver of precision medicine, promising individualized drug selection and dosing. Traditionally, pharmacogenetic profiling has been performed using targeted genotyping focusing on known variants. To date, the key inputs of panel long-read sequencing have not been validated in routine clinical practice. We constructed a long-read targeted pharmacogenomic panel with dynamic, adaptive sampling to maximize information gain, reduce time to answer, and increase confidence in called genotypes. Among the genes we focused on the most important genes modulating the drug pharmacokinetics, such as CYP2D6 and NAT2 genes. In total, 25 samples were sequenced. Coverage was uniform for all samples with an average depth of >100x. When compared to reference short-read results from Hospices Civils of Lyon (HCL) certified assay, the phasing was at a high level in the phased target regions. No major discordance was observed for gene haplotyping, leading to no major discordance in terms of functional phenotype prediction. We demonstrated that long-read-based pharmacogenetic profiling significantly improved and resolved ambiguous haplotype resolution. Collectively, these results indicate that targeted long-read sequencing enables comprehensive detection of genetic variation, including SNPs, indels and structural variants, and limits ambiguous haplotype resolution by direct phasing, without the need for statistical phasing as required by the short-read method. Long-read sequencing as the predominant method for future genetic diagnostics and pharmacogenetic profiling, could provide data quality and potentially improve patient care at an ‘acceptable price’ in clinical practice.

Biography

Professor Léa Payen, PharmD, PhD is currently a Professor in Toxicology and Biochemistry, and a medical and research fellow at Hospices Civils of Lyon (HCL) and Claude Bernard University Lyon I (UCBL1). She leads the research on liquid biopsy and pharmacogenetics in solid thoracic tumor and psychiatry in routine management of patient and translational studies at HCL. The HCL biobank is a large-scale research support platform set up to improve clinical research and public health. Professor Payen aims to improve fundamental and translational studies in several types of cancers and pharmacogenomics.