Scientists Describe Use of SMRT Sequencing for PGx Application

A new article in Drug Discovery & Development from Stuart Scott and Yao Yang at the Icahn School of Medicine at Mount Sinai offers a compelling look at enhanced analysis of the CYP2D6 gene. The article, “Long-Read CYP2D6 Sequencing Enables Full Gene Characterization and Novel Allele Discovery,” describes the Mount Sinai team’s efforts to provide better resolution of this region with SMRT Sequencing.
The gene is important for drug development because the enzyme it encodes is involved in metabolizing nearly a quarter of all drugs frequently prescribed today. According to the article, “Variants within this gene can help predict how patients respond to medications ranging from painkillers to antipsychotics, which makes CYP2D6 an essential gene to consider when implementing pharmacogenomics into clinical care.”
The scientists turned to PacBio long-read sequencing to characterize this genomic region because the gene includes many deletions, duplications, and other structural variants which would be challenging to capture using other technologies. To date there are more than 100 known variations of the allele and new ones are constantly discovered. Most methods for querying the gene are limited by the number of alleles they can recognize or by their inability to capture complex structural variations and DNA duplications. Implementing SMRT Sequencing, however, allowed the scientists to detect all CYP2D6 alleles with great accuracy as well as to phase alleles.
While validating the new SMRT Sequencing pipeline for CYP2D6 analysis, the scientists discovered three novel alleles. “In fact, ~20% of the samples used to evaluate CYP2D6 SMRT sequencing were revised to either a non-genotyped or novel star (*) allele,” Scott and Yang write, “which highlights how long-read sequencing can reveal previously unrecognized variation in well-studied genes and specimens that were previously tested by other technologies.”
The authors conclude that establishing this approach for CYP2D6 analysis could address some of the consistency problems that have been seen in previous pharmacogenomics studies, which likely have been caused by different allele frequencies among patient populations. They recommend that long-read CYP2D6 analysis should be used for diverse populations in clinical trials to improve the community’s understanding of the natural variation in this gene across ethnicities. This information will be essential for developing better prescription and dosing guidelines for all patients.