Currently there are over 120 drugs that have genetic information in their package labeling and deemed as being actionable by FDA guidelines, some with “black box” warnings where an action is assigned. Of these drugs, 23 fall within the top 200 most commonly prescribed drugs. The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the FDA provide guidelines that enable the translation of genetic laboratory test results into actionable prescribing decisions that promote the safe and eff ective use of specifi c drugs. It is estimated that during a person’s lifetime 96% of consumers will be prescribed a drug that has actionable PGx information , yet few of these tests are currently used in any clinical settings. There have been a number of major barriers to implementation of pharmacogenetic diagnostics, including lack of knowledge by clinicians, but a major factor is the availability and cost of tests, reimbursement, and delay in return of results. Here, we address how to capture PGx data effi ciently, in a cost-eff ective and broadly applicable manner. We have designed an assay set that covers the pharmacogenetic “actionable genome”, that is genes that have guidance (CPIC) for the use of the genetic information. We have used a molecular inversion probe (MIP) platform to develop a custom pull-down sequencing assay (PGx1). Designs were performed for twenty-one genes using MIPgen resulting in 1800 probes, with each probe optimized to specifi cally capture 112 bp of sequence. MIP sets were tested and re-designed or re-balanced for optimal performance. The resultant set covers all coding regions, exon/intron boundaries, and 1 kb of upstream sequence (amounting to 120 kb of sequence). PGx1 tests in a 48 DNA sample multiplexed MiSeq sequence run show that the assay provides greater than 35X average coverage. As a clinical diagnostic tool however, there are only specifi c polymorphisms that have direct guidance; sequencing depth was optimized for these polymorphisms. 42 polymorphisms have been validated in a CLIA/CAP environment such that the genotypes can be directly reported as a clinical result. These genes/polymorphisms cover pharmacogenetic impact across a number of diff erent disease/drug indications, eg. cardiovascular, pain, psychiatric. We have used this assay as an educational tool with PharmD students, and in high-risk populations (cath lab patients) to explore pharmacoeconomic analysis.
