Technical aspects and costs have limited the use of personal genome analysis and whole genome sequencing to major research institutions and large clinical collaborations. However, these barriers are falling quickly and a critical tipping point is being reached whereby such analyses will soon start emerging into clinical care.
By Dr. Peter Hulick
In the time leading up to this year’s annual meeting of the American Society of Human Genetics, three laboratories announced the availability of clinical personal genome analysis via sequencing of the entire exome. Two laboratories require testing to be conducted and ordered through a medical professional. However, one lab offers the option of using a direct-to-consumer genetic testing company, thus allowing anyone to potentially gain access to their genome sequence without going through their primary care provider or other medical professional first.
Typically, when a genetic test is ordered, such as BRCA1/2 for hereditary breast and ovarian cancer, the individual gene or a small panel of genes related to a particular diagnosis are sequenced. This sequencing can be performed using a parallel or stepwise approach based on the potential likelihood for identifying a causative mutation, therefore minimizing cost, maximizing yield, and limiting the chance of finding a "variant of uncertain significance" for which the clinical implications are unknown. Thus, it is a very targeted approach to genetic testing.
In contrast, whole genome analysis of the exome yields the DNA sequence of every exon (part of the gene which is translated into a protein) in the entire genome that consists of over 20,000 genes, representing tens-of-millions of DNA bases. Thus, instead of limiting the information to a specific gene or genes and condition (for example BRCA1/2 status in a patient with breast cancer), one will obtain data for all genes regardless of whether or not they are related to breast cancer.
How will internists be affected by the availability of personal genome analysis? Part of the answer will depend on the uptake of testing and how the testing is obtained (clinical practice versus direct-to-consumer).
The direct-to-consumer route will likely be limited at first to a pilot program involving only existing consumers. But presumably the program will be expanded and we are likely to see direct marketing to our patients. Some patients may choose to discuss their results with their primary care physician, but prior experience with direct-to-consumer genomics testing has demonstrated that the majority of individuals do not discuss results with their physician. Thus, our patients may be acquiring important knowledge that could affect clinical management without our realization, highlighting the importance of being proactive in discussing the concept, risks, and limitations of personalized genomic medicine with our patients.
Every physician has patients where something, such as breast cancer, "runs in the family." The clinical availability of personal genome analysis through sequencing the whole exome allows a physician to order a single test that can give us information on all the genes, including ones known to be linked to breast cancer.
As tempting as this may be, there are many potential pitfalls that need to be addressed by the medical community before one can advocate for the routine use of such testing. Will the results have a meaningful impact on patient care and management? Can a patient opt out of knowing particular results (for example, genes associated with increased risk for Alzheimer’s disease)?
With single gene testing, there is always a chance of finding a "variant of undetermined significance" for which clinical interpretation is difficult. This possibility will be amplified significantly with personalized genome analyses, given the sheer number of genes interrogated. Finally, how will these data be stored? Current electronic medical records are not designed for single gene test results, let alone whole genome analysis.
These questions are currently being debated within the medical genetics community, but it will be important to bring primary care providers into these discussions. As personalized genome analysis is integrated into clinical practice, the physician-patient relationship will be critical for educating consumers about the potential and shortcomings of this new technology.
Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill. and a clinical assistant professor at the University of Chicago. He reported having no conflicts of interest.