NEW YORK (GenomeWeb) – Mayo Clinic's Center for Individualized Medicine has been rolling out genomic testing for its patients, integrating genomics into electronic medical records, and participating in clinical trials that focus on delivering personalized medicine.
The center recently published a paper on its experience with diagnostic exome testing in the Mayo Clinic Proceedings and launched an effort to sequence 84 genes related to pharmacogenomics in 10,000 patients in collaboration with Baylor College of Medicine. It published the results of the first 1,000 patients this month in the Journal of Molecular Diagnostics.
In addition, the center offers NGS-based panel testing for some cancers and cardiovascular disorders and is developing panels for neurology and gastroenterology disorders. Recently, it began a pilot predictive genomics program where it offers whole-genome sequencing through its executive health program for patients willing to pay $9,500 out of pocket. It is also participating in a PGx clinical trial to see whether knowing PGx status prior to being prescribed a cardiovascular drug improves outcomes.
Keith Stewart, director of Mayo's Center for Individualized Medicine, spoke about these projects at the Molecular Medicine Tri-Conference in San Francisco last month and in a follow-up interview with GenomeWeb. The ultimate goal, Stewart said, is to implement a clinically relevant whole-genome sequencing test that costs around $500.
Predictive genomics
Stewart said that as part of Illumina's Understand My Genome program, he and a handful of other Mayo employees had their whole genomes sequenced.
During his presentation at Tri-Con, he said he was initially "underwhelmed" by the results. He learned that he was a carrier for spinal muscular atrophy, hemochromatosis, Neimann Pick disease, and galactosemia — none of which has manifested in his family. In addition, he learned pharmacogenomics results — finding out he was a rapid metabolizer of tricyclic antidepressants and statins, but a slow metabolizer of the anticoagulant warfarin.
However, upon further reflection, he realized it wasn't the variants for which he was positive that were interesting, it was the variants for which he was negative.
For example, he learned he was not a carrier of a disease for which he does have a family history. In addition, he learned that he was negative for "1,600 hereditary conditions, including cancer and neurodegenerative conditions," meaning he has no need for future genetic screening for those conditions. If he gets a blood clot, he won't need genetic testing to determine what drugs he is able to take. "It will make my future healthcare better," he said.
Of 25 other Mayo employees who had their genomes sequenced, five had significant medical findings, he said, including one who found out he was a carrier for cystic fibrosis.
Although it is still not affordable to sequence everyone's genomes, he said, that is the direction that the Mayo Clinic is moving toward. To understand patient demand, the center already offers whole-genome sequencing as part of its executive health program, and about 100 individuals have signed up so far. The cost is $9,500 and Stewart said patients who opt for it can find out cancer predisposition and the risk of developing neurodegenerative disease, as well as pharmacogenomics information and carrier status for other Mendelian disorders.
He said the offer is more of a pilot to see what the uptake is, whether clinically useful information can be delivered effectively to patients, and how patients respond. The vast majority of patients are relatively healthy, he said, and just curious.
But moving forward, researchers at the Mayo Clinic are trying to figure out how to scale this up and bring the cost down. In 2015, he said, the clinic sequenced about 600 whole genomes, and has now sequenced about 1,000 whole genomes, but by 2020, the goal is to sequence 50,000 genomes — the entirety of its current biobank.
PGx genes
Stewart said the biobank contains samples from 50,000 patients who have consented to broad research studies. The 1,000 samples that have had whole-genome sequencing done so far were purely for research, Stewart said, but in the future, the clinic will look to report back some information into medical records of consenting patients.
As a first step in this direction, the group, in collaboration with Baylor College of Medicine, is sequencing 84 genes related to drug metabolism in 10,000 patient samples. Testing was done by NGS for 84 genes, but the researchers used a variety of methods for the CYP2D6 gene is because it is difficult to assess via NGS due to the presence of a highly homologous locus nearby. For the CYP2D6 gene, they started with the Luminex Tag-It mutation detection kit, followed by copy number variant assays or single-gene sequencing if needed.
All the patient samples are from Mayo's biobank, but both Baylor and Mayo perform the sequencing. One advantage of having patient samples with detailed clinical information, Stewart said, is that the patients who consented to the study were all deemed likely to be prescribed a statin in the next three years.
The patients consented to have information from five genes — SLCO1B1, CYP2C19, CYP2C9, VKORC1, and CYP2D6 — deposited into their medical records. Results from the five genes were delivered to patients' medical records in such a way that alerts are triggered when a physician prescribes a drug that will interact with one of the patient's PGx variants.
In the recent Journal of Molecular Diagnostics study, the team found that of the first 1,000 patients, 99 percent had an actionable variant in at least one of those five genes, providing "evidence in favor of preemptive PGx testing," particularly for individuals taking multiple medications, the authors wrote. In addition, they noted that they plan to follow the patients prospectively to gather additional data on the utility of preemptive PGx testing.
Stewart said that Mayo is also working with spinout Oneome to develop methods to deliver PGx data to physicians in a way that they know what to do with the information. In order to boost education on PGx variants at all levels, he said, Mayo has built pharmacy education models and has hired a pharmacist who is able to explain PGx results.
Clinical exomes and panels
Like many other major academic medical centers, the Mayo Clinic offers clinical exome sequencing for patients with unknown genetic diseases and with advanced cancers.
Mayo has some sequencing capacity in its own labs, but typically contracts out its clinical exome sequencing, primarily to Baylor Miraca Genetics Laboratories.
As described in the recent Mayo Clinic Proceedings report, during the first 18 months of operation, Mayo received consultation requests for 82 patients andended up providing exome sequencing for 51. A handful of patients did not meet the criteria for testing — either because their phenotype was poorly defined, further evaluation determined the disease was not genetic in origin, or because its onset occurred later in life. In addition, a number of patients opted not to get tested because although the Mayo team approved them for testing, their insurance company did not, and the out of pocket costs would have been too high.
Of the 51 patients who were tested, 44 were sequenced at Baylor for an average cost of $7,000 each, including confirmatory testing in parents and insurance preauthorization. Ambry Genetics performed testing for five individuals for $5,800 each, which included insurance preauthorization, trio sequencing, and confirmatory testing, and GeneDx sequenced two patients for $9,000 each, including insurance preauthorization, trio sequencing, and confirmatory testing.
The Mayo Clinic covered costs for the first nine patients, insurance covered the full cost with no out-of-pocket fees for 36 patients, and 16 patients received partial coverage.
Overall, exome testing diagnosed around 29 percent of the patients, similar to, if not slightly lower than, other laboratories. The average age of patients was 21 years, significantly older than most laboratories that primarily test pediatric patients.
Stewart described one example of a patient who at 18 months could not stand up straight. The family went years without knowing what was wrong and their son's problems continued to get worse. Finally, as a teenager, exome sequencing found the molecular cause, and he was diagnosed with episodal ataxia. He is now on medication that enables him to function normally, even play sports.
Stewart said they have also been able to describe new diseases and understand wider spectrums of known diseases.
The Mayo Clinic also offers diagnostic tumor exome sequencing for patients with advanced cancer, which Stewart said has helped get patients on the appropriate treatments, although he added that to be really effective, such testing needs to be done earlier.
In addition, Mayo has been offering a number of different panel tests. Most recently, it launched several panels for cardiovascular disorders, including a 13-gene test for Marfan syndrome, a 30-gene dilated cardiomyopathy panel, a 13-gene Long QT syndrome panel, a 26-gene hypertrophic cardiomyopathy panel, a 9-gene arrhythmogenic cardiomyopathy panel, and a 55-gene comprehensive panel.
Stewart said the team is now in the process of developing panels for neurological disorders like epilepsy, neurodegenerative disease, peripheral neuropathy, and more, and plans to soon move into the area of gastroenterology.