In the CPGM’s Genomic Medicine Course, PGET is used to complement lectures and discussions, directly exposing participants to the magnitude of nonpathogenic human genetic variation and the challenges associated with variant interpretation.
PGET can engage and motivate participants as they learn to use analysis software and variant databases. Genomic sequencing commonly identifies variants of unknown significance (VUS) and rare variants that may be associated with unknowns, such as pleiotropy (the effect of a single gene on multiple phenotypic traits), epistasis (gene–gene interactions), phenotypic heterogeneity, and incomplete penetrance. An additional complication is that variant interpretation may change. A VUS today may become interpreted as benign or pathogenic as genomic reference databases improve. These challenges can be frustrating for clinicians and researchers. In our experience, hands-on exposure to NGS analysis results in a greater tolerance for VUSs and a more sophisticated appreciation of variant ambiguity among our providers.
Approach to Personalized Genomic Education Testing (PGET)
Participants will be offered the unique opportunity of electing to have a NGS panel run on themselves, which can profoundly illustrate teaching points about normal human variation, variants of unknown significance, and unanticipated findings. The panel targets 571 genes that cause childhood onset disease. It was developed by the CPGM for clinical use and has also been utilized for the PGET component of our preexisting genomics course. The panel is optimal for this application because it does not include adult onset disorders, making unexpected diagnoses of a participant unlikely.
Prior to the course, the participants will be assigned a numeric identifier, so their sample can be sent to the CPGM in a de-identified manner for sequencing. Participants will also be provided with an Institutional Review Board (IRB)-approved information sheet that details the following: the methods used for sample and data handling, the likelihood of carrier status detection, and the option of using a preexisting de-identified data file in place of PGET. The de-identified samples are sequenced and analyzed by CPGM personnel who are blinded to the identity of the participant. Course participants will then analyze their own results in a workshop and be allowed to compare their findings to those of an expert reviewer; all findings are then discussed in private with a genetic counselor. In the event participants elect not to have their own panel run, they will also be scheduled to meet with a genetic counselor where the discussion will focus on what the results from the de-identified data would have meant.