Genomic testing has become standard of care for a wide spectrum of diseases, but it isn’t always clear which test is the “best test” for the disease being investigated. Some diseases and/or phenotypes may benefit from single gene analysis, whereas others may benefit from casting a wider net. With so many options to choose from—ranging from FISH, SNP, chromosomal, microarray, cell-free DNA (cfDNA), sequencing, deletion/duplication—navigating this landscape can seem as difficult as walking into Mordor.

Fortunately, the Monday session, “Laboratory Consultations in Genomic Medicine: Case-Based Learning” equipped laboratory professionals with the practical knowledge they need so that they can provide genomic testing advice for these commonly asked questions. The moderator and first speaker of the session, Jason Park, MD, PhD, DABCC, is a pathologist at UT Southwestern Medical Center. At his hospital there is a mixture of genomic tests that are performed on-site and genomic tests that are referred out.

He observed that laboratorians can expect that there will be “common questions that clinicians ask regarding genomic test results,” including which test to order, which laboratory to use, and how to interpret the result. “The results of the tests are not just informative for future disease, but they also inform current treatment decisions, current diagnoses…Getting it right is very important,” he said. “Patients expect us to be able to explain when these results are not clear.”

Park focused on the analytical portion of genomic testing, including potential laboratory issues and the emerging methods that should be considered in clinical practice. He began by presenting an overview of the different genomic testing options, including chromosomal microarrays, FISH, Sanger sequencing, and next-generation sequencing. Park also discussed the varying diagnostic yield of these options, and he provided a comparison between targeted genomic panels, versus exome, versus whole genome sequencing.

Park also used clinical cases to highlight the differences between genomic tests. In his first case, he explored how a patient can have a germline genomic test with different results from different labs. In this case, the exome test was falsely negative because of lack of coverage. The genes were in the panel but incompletely analyzed. When selecting a laboratory for referral testing, Park emphasized that genes targeted is not necessarily equal to the genes evaluated: Complete coverage is the foundation of quality. When the results are discrepant or unexpected, his laboratory will call the referral laboratory and check if the coverage is complete in the genes and region of interest. His second case highlighted the importance of discussing test results that do not make clinical sense in order to identify potential laboratory errors.

Whereas Park focused on the analytical portion of the testing process, Garrett Gotway, MD, PhD, a medical geneticist at UT Southwestern Medical Center, focused on the post-analytical portion, namely, how to interpret test results and read reports.

Gotway’s talk also used a case-based approach. His cases highlighted how variant classification is a dynamic process, where variants are reclassified as more data becomes available. He highlighted the implications of reclassification and made the case for frequent reevaluation of variants. His laboratory recommends that providers be contacted if reclassification is clinically significant. He also suggested that clinicians re-evaluate variants before follow-up visits. To aid in this process, he introduced users to ClinVar, the public archive detailing germline and somatic variants and their phenotypes.