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Geisinger Begins Returning Clinically Actionable Exome Sequencing Results to Patients

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NEW YORK (GenomeWeb) – In an attempt to figure out how to best implement clinical sequencing within a health system, Geisinger Health System has begun returning clinically actionable results in a set of genes to patients enrolled in the MyCode Community Health Initiative.

The program is part of a five-year research study that kicked off at the beginning of last year and is being conducted by Geisinger and Regeneron Pharmaceuticals, which is performing the sequencing.

The goal is to sequence the exomes of 250,000 patients within the Geisinger Health System both for research purposes and to identify clinically relevant variations that will impact patients' care. Geisinger is returning results from 76 genes to patients, their primary care providers, and depositing the information in patients' electronic medical records.

During a presentation at this month's Festival of Genomics conference in San Mateo, California and in a subsequent interview with GenomeWeb, Adam Buchanan, a clinical investigator at Geisinger, provided an update on the program.

Buchanan noted that the population that Geisinger serves is ideal for this type of study because it is diverse, stable, and there is a plethora of clinical and phenotypic data in patients' EMRs. Geisinger serves nearly 3 million people in 44 counties in central and northeast Pennsylvania, and the populations are both older and poorer relative to the national average. In addition, less than 1 percent of the population moves out of the Geisinger Health System annually, so there is data from large multi-generational families.

Currently, about 100,000 individuals are enrolled in the MyCode Community Health Initiative biobank and around 1,000 individuals enroll per week, Buchanan said.

Prior to launching the initiative, Buchanan said the team did focus groups with patients to try to figure out whether they wanted their own genetic information, and if so, how they wanted it to be returned.

Overwhelmingly, Buchanan said, patients said they wanted the ability to access their own information, but that they also wanted their physician to have the information.

Based on that feedback, Buchanan said Geisinger developed a protocol through which, if a clinically actionable variant was found, Geisinger first alerts the physician of the finding. Five days later, it notifies the patient that testing of that patient's biobank sample has found something medically important and requests that the patient contact Geisinger.

Patients can then either get in touch directly with Geisinger, which will provide counseling and return of results, or contact their physician, or choose not to deal with it at all. Regardless, the information is also deposited in the patient's EMR.

"We let the patient guide the process," Buchanan said.

Geisinger chose 76 genes that account for 27 conditions in which to return actionable findings. Those 76 include the 56 genes recommended for screening by the American College of Medical Genetics and Genomics. Seventeen of the 20 additional genes are genes related to the same medical conditions as ACMG's 56 genes, which the ACMG had left off their original list because the genes were less commonly associated, Michael Murray, Geisinger's director of clinical genomics, told GenomeWeb. The three other genes accounted for two additional conditions, a metabolic disorder and an autosomal dominant condition that causes abnormal blood vessel formation. Both "meet the basic criteria of the ACMG list, in that they're monogenic, highly penetrant, and there's something you can do for the patient if you find out they have that gene," Murray said.

The exome sequencing itself is performed by Regeneron in a research setting. If a potential variant is found in one of the 76 genes, a second sample from the biobank is requested and is tested for that specific finding in a CLIA-certified laboratory.

As of Oct 30, the Geisinger team had returned 15 results to patients, and Buchanan said that the team anticipates that around 2 percent of patients tested will have a pathogenic variant.

Thus far, Buchanan said that three conditions have accounted for about half of the findings — familial hypercholesterolemia, hereditary breast and ovarian cancer variants, and Lynch syndrome mutations.

Interestingly, the early results suggest that prevalence of familial hypercholesterolemia may be higher in Geisinger's patient population at 1 in 175 than that of the general population, which has been estimated at anywhere between 1 in 500 to 1 in 299 in the US. Whether or not this is a real result is still too early to say, however, said Murray.

However, he said, that since traditionally, the condition was only diagnosed when patients presented with symptoms and phenotypes of the disease, as opposed to screening for it based on genetics, the lower prevalence estimates may have missed some patients.

"Some of those patients would not have stood out clinically as classic familial hypercholesterolemia cases," he said. "It's an expansion of our understanding of the phenotypes that are associated with the genotypes." And, he said, he expects to see similar trends for other diseases as well.

Buchanan added that for about 10 percent of the patients who have a variant in a gene indicating familial hypercholesterolemia, there is nothing in that patient's medical record suggestive of the condition.

Geisinger has genetic counselors, medical geneticists, and specialists — for example, in cancer or cardiovascular disease — that are available to the patient and/or the patient's primary care doctor, Murray said.

There is not standard amount of time that a genetic counselor will speak with a patient about his or her results since it is very patient-driven. "In any particular case, the patient or primary care physician might defer to a specialist or a genetic counselor, or might not," Murray said. "We're tracking all that, though," he said. "The early interactions we've had with patients have been typical of an office visit or consultation, about 45 minutes to an hour."

Geisinger will also offer testing to patients' family members who may also be impacted by the genomic findings, so the number of patients tested and counseled could rapidly expand, Murray said.

"If we have 250,000 patients that undergo sequencing, 5,000 will have a result, and there will be potentially another 30,000 relatives that we'll have to follow up with," Buchanan said.

Buchanan said that there are likely five categories of patients for whom results will be returned.

One group will include patients who already know the information, either because they have already been diagnosed with the disease or because they had already received genetic testing due to family history. A second group will include patients who had been showing symptoms of the disorder but had not received a diagnosis yet for their condition. A third group of patients would have a phenotype of the disorder that had not yet reached a level at which a clinical diagnosis could be made. For a fourth group of patients, the genomic information will come as a complete surprise because patients had not yet developed symptoms, but will in the future. And finally, some patients will never develop symptoms of the disorder for which they have a pathogenic variant.

Thus far, Buchanan said one of the major lessons the team has learned in returning results to patients is that sometimes "there is a bit of a gap in terms of what we think we're saying and what's being heard."

For example, he said, one woman who was found to have a BRCA1 mutation said that this was information she already knew. However, at the time she initially received the result, she had not gotten a lot of genetic counseling support. When the result was returned from Geisinger, her first instinct was to Google the mutation, where she said she found information about leukemia. So, when she did contact Geisinger, she asked about her leukemia risk. In addition, Buchanan said, Geisinger also found out that she had a daughter who had not been tested for BRCA1.

"It was an instance where the outcome we hoped would happen, happened," in that the woman did seek genetic counseling from Geisinger, "but for a reason we did not anticipate."

In another case, Geisinger returned results to man about hypercholesterolemia. He told Geisinger that the information was not important to him because he already knew he had high cholesterol, so knowing the genetic cause was not important.

"That message of, yes, you may know about your high cholesterol, but now we know a reason for it and that reason may be important for your care and your relatives, did not get across," Buchanan said.

There have been other communication challenges as well, Buchanan said. About half of the patients have an external primary care physician, and Geisinger does not have access to those medical records, "so it's not always clear whether that patient is getting appropriate follow-up care," Buchanan said.

He added that in order to improve on this aspect, Geisinger is looking to hire a liaison for external practices.

Murray said that Geisinger will continue to make improvements to the program. One major focus is to make improvements to how it continues to provide follow-up support and long-term care for patients.

In addition, he said, Geisinger is also considering expanding the number of conditions for which it screens to include additional monogenic conditions as well as pharmacogenomic variants and carrier status.

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