Genotyping Reveals Relevant, Incidental Pharmacogenomic Findings

Clinically relevant pharmacogenomic findings are seen in single nucleotide polymorphism (SNP) genotyping and exome sequencing data, according to a study published in Genetics in Medicine. These findings suggest the need to refine strategies for reporting pharmacogenomics incidental findings as a means to improve patient care and to further personalize treatment.

The American College of Medical Genetics and Genomics (ACMG) has focused on disease-associated genes, but pharmacogenetic incidental findings can be clinically actionable and hold potentially significant medical benefit given the possibility of life-threatening adverse drug reactions or therapeutic inefficacy.

Pharmacogenetic analysis was performed on a research basis for individuals participating in the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) between 2009 and 2014. SNP chip analysis was performed on 1,101 individuals (from 308 families, including 355 affected individuals), while a subset of these participants underwent exome sequencing (645 individuals, including 182 affected, from 158 families).

The Pharmacogenomics Knowledgebase (PharmGKB; 868 pharmacogenetic loci) was used to identify incidental findings based on its listing of variant–drug associations. Combined, the SNP chips and exome sequencing provided coverage of 65 percent of the SNPs in the PharmGKB database and 81 percent of the PharmGKB 1A and 1B SNPs (top two levels of variants based on evidence).

The researchers found that SNP chip sequence data identified 395 sequence variants, including 19 PharmGKB 1A and 1B variants, while exome sequencing data uncovered 388 variants, including 21 PharmGKB 1A and 1B variants. No participants had been prescribed a medication associated with a PharmGKB 1A or 1B category variant they carried. However, five pharmacogenomically relevant incidental variants were identified in nine individuals, although these associations ranked lower in PharmGKB—category 2 or category 3 associations. Yet, these variants altered efficacy of a prescribed medication. Three of the variants were detectable with both the SNP chip and exome sequencing technology and two were detectable only by exome sequencing.

“Despite the small size of the NIH UDP patient cohort, we identified pharmacogenetic incidental findings potentially useful for guiding therapy,” writes co-author Murat Sincan, M.D., from the NIH’s UDP (Bethesda, Md.). “Consequently, groups conducting clinical genomic studies might consider reporting of pharmacogenetic incidental findings.”

In the present study, the choice to report an incidental variant to the participant was made by the clinical team, which elected not to return PharmGKB category 2 or 3 variants. Several reasons were cited.

“The study consent reflected routine practice from the early days of the application of genome-scale sequencing to medical diagnostics—only DNA variants that might contribute to the test indication were to be returned.” “Second,” the authors write, “current ACMG guidelines do not include such variants among those recommended to be returned. The UDP recognizes that these are areas of intense debate in the literature and elsewhere; the program is prepared to adjust its practice as the standard of care evolves.”

Takeaway: Despite a current focus to date on disease-associated, genetic incidental findings, pharmacogenomic incidental findings may be detectable using SNP chip or exome sequencing technology and may be clinically relevant.