Direct Comparative Analysis of a Pharmacogenomics Panel with PacBio Hifi Long-Read and Illumina Short-Read Sequencing.

BACKGROUND

Pharmacogenetics (PGx) aims to determine genetic signatures that can be used in clinical settings to individualize treatment for each patient, including anti-cancer drugs, anti-psychotics, and painkillers. Taken together, a better understanding of the impacts of genetic variants on the corresponding protein function or expression permits the prediction of the pharmacological response: responders, non-responders, and those with adverse drug reactions (ADRs).

OBJECTIVE

This work provides a comparison between innovative long-read sequencing (LRS) and short-read sequencing (SRS) techniques.

METHODS AND MATERIALS

The gene panel captured using PacBio HiFi sequencing was tested on thirteen clinical samples on GENTYANE's platform. SRS, using a comprehensive pharmacogenetics panel, was performed in routine settings at the Civil Hospitals of Lyon. We focused on complex regions analysis, including copy number variations (CNVs), structural variants, repeated regions, and phasing-haplotyping for three key pharmacogenes: , and .

RESULTS

Variants and the corresponding expected star (*) alleles were reported. Although only 38.4% concordance was found for haplotype determination and 61.5% for diplotype, this did not affect the metabolism scoring. A better accuracy of LRS was obtained for the detection of the haplotype in the presence of the duplicated wild-type form. A total concordance was performed for TA repeat detection. Direct phasing using the LRS approach allowed us to correct certain profiles.

CONCLUSIONS

Combining an optimized variant-calling pipeline and with direct phasing analysis, LRS is a robust technique for PGx analysis that can minimize the risk of mis-haplotyping.