Bringing Whole Genome Testing to the Clinical Setting

Led by co-directors Euan Ashley, MD and Jason Merker, MD, PhD, a team comprised of clinicians in multiple disciplines from Stanford University Medical Center — bioethicists, genetic counselors, bioinformaticians, basic and translational researchers and other experts in a variety of specialties — are parsing the genomes of 100 patients at Stanford Hospital & Clinics and Lucile Packard Children's Hospital as part of the new Clinical Genomics Service. The long-term goal of the program is to help doctors better diagnose, and in some cases even treat, genetic disorders by leveraging the power of genome sequencing.

The pilot program is open to a limited number of patients whom doctors believe may benefit from genome sequencing, such as patients with "mystery" diseases (typically children), unexplained hereditary cancer risk, inherited cardiovascular or neurological disease and patients with severe, unexplained drug reactions. The service has enrolled about 20 patients since launching in January.

Stanford Hospital & Clinics, Lucile Packard Children's Hospital and the Stanford School of Medicine are funding the initial 100-patient pilot to determine the efficacy of using genome sequencing on a broader population of patients in the future. "We have been trying to determine when would be the right time to start doing this in the hospital," says Ashley, associate professor of medicine and of genetics. Those involved in the development of this program agreed that the appropriate place to start would be in patients with rare diseases, where a patient and his or her family may have a genetic condition that has thus far eluded diagnosis, he adds. "That ability is here today, and the power of what we can offer is quite significant." Just over the horizon, Ashley foresees using genome sequencing to help prescribe therapies more generally in a personalized manner.

Gene detectives go to work

Following selection for the program, patients will undergo a research consent process before undergoing the blood draw to initiate testing. This is a particularly important step of genome sequencing since it will often uncover uncertain results pertaining to disease risks, says Megan Grove, MS, LCGC, a genetic counselor for the Clinical Genomics Service. There are many important questions to consider before undergoing genome sequencing, she adds, because of the types of genetic results that may be identified, patient preferences for which types of results to receive, the limitations of the testing and privacy concerns. 

Once a patient's genome has been sequenced, the interpretation team, comprised of bioinformaticians, biocurators, molecular pathologists and genetic counselors, will comb through millions of raw data points, comparing significant genetic variants with available disease and genetic information and identifying the genetic variations deemed important enough for follow-up. These are the points that require additional, manual analysis and interpretation, says Merker, assistant professor of pathology.

Because the Clinical Genomics Service is enrolling patients with complex, and often multi-system diseases, the biocuration team will start by focusing the analysis on specific areas of the genome where the answers are most likely to lie. In some cases, there may be a clear answer that is identified which explains the patient's condition at the genetic level. In most cases, however, the team will need to closely inspect several suspicious genetic variants that look like they may be involved in disease, but require follow up testing to learn more information.

When the data analysis is complete, the team will present their findings to a review board that includes members of the Dean's Advisory Committee on Clinical Genomics as well as the referring physician and any disease domain experts.

Challenges remain

Although genome sequencing can provide life-changing discoveries, there are still significant challenges that must be overcome before it can be used routinely in the clinical setting. That's one important finding from a recent study on genome sequencing at Stanford. Specifically, the Stanford researchers found that individual risk determination would benefit from improved sequencing accuracy in disease-associated genes. Also, each full genome analysis requires up to 100 hours of manual analysis to assess the potential impact of each variant.

"Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized," says Ashley. "It's only because of the foresight of the leadership at Stanford that we're able to do this," he adds. "They realized that this was something that could not only transform health care where we are currently, but that Stanford could be a leader and help show the world how to do this and how to do it right. Genome sequencing has the power to be absolutely transformative in the clinical setting."

To refer a patient

The pilot program only takes referrals from within Stanford Hospital & Clinics and Packard Hospital. To refer a patient for consideration, email Megan Grove, MS, LCGC, at mgrove@stanfordmed.org. The Clinical Genomics team will determine whether the patient's case is suitable for sequencing.

By Grace Hammerstrom