NEW YORK (GenomeWeb) – Results from Geisinger Health System's MyCode Community Health Initiative, combined with the project's ability to recontact patients, may help clarify the pathogenicity and penetrance of variants in disease-associated genes, according to researchers coordinating the initiative.
"We're excited by the fact that we have the ability to recontact patients and bring them in for further evaluation, or survey them over the phone, or whatever is needed to answer a question," Michael Murray, director of clinical genomics at Geisinger's Genomic Medicine Institute, told GenomeWeb.
Earlier this week, Geisinger said it has recruited more than 100,000 participants for the MyCode initiative, much faster than originally expected. When Geisinger and its partner Regeneron Pharmaceuticals first announced the project in early 2014, the plan was to collect and analyze 100,000 samples from patient volunteers over five years.
As of last month, Regeneron had already sequenced the exomes of more than 60,000 participants, and the new goal is to sign up at least 250,000 patients from the Geisinger Health System, making it one of the largest precision medicine projects to date. Many participants turn out to be related, Murray said, which was not a recruitment goal, but which can serve as a powerful tool for analyzing how genotypes and phenotypes segregate in families.
Patients recruited to MyCode provide a blood sample, which undergoes exome sequencing at the Regeneron Genetics Center. Genomic results are then correlated with their electronic health records to find new associations between genetic variants and disease. In addition, Geisinger returns potentially medically relevant results for a limited number of conditions to participants.
The initiative started returning results to patients last year, focusing on mutations in 76 genes associated with 27 conditions.
So far, the program has returned pathogenic or likely pathogenic variants to approximately 100 patients, focusing almost exclusively on three conditions it identified as having the greatest impact on public health: Lynch syndrome, familial hypercholesterolemia, and hereditary breast and ovarian cancer.
"It's hard to start a program and deliver on 27 conditions at once, so we had to pick some priorities," Murray said, noting that the three conditions are expected to be the most frequent ones. In addition, "we could build on existing infrastructure to deliver these relatively easily, compared to some of the less common conditions," he said, which will be added to the program over time.
Based on the initial findings, the Geisinger researchers now believe that between 2 and 4 percent of MyCode participants will eventually receive a result. By the end of this year, they anticipate returning findings to hundreds of participants for each of the three conditions and are preparing a publication about their initial experience.
In addition to providing participants with genetic risk information, Murray and his colleagues also believe the results may help clarify the clinical significance of variants that are currently disputed, as well as the penetrance of known pathogenic variants.
For example, while trying to identify returnable results, they came across variants of unknown significance in a number of genes, which did not meet their criteria for delivery to patients. "As you know, this variant of uncertain significance problem is a real problem for the field," Murray said.
One of them was a variant in the LDL receptor gene, which they found in more than 20 patients in their cohort. Mutations in LDLR are associated with familial hypercholesterolemia, but this particular variant had only been submitted a few times to the ClinVar database, with conflicting interpretations: one lab reported it as pathogenic, a second lab as benign, and a third one as uncertain, Murray said. With conflicting interpretations, the variant is only rated with a single star in ClinVar.
By looking at the EHRs of those patients who harbor the variant, and potentially bringing them in for further clinical assessments, the Geisinger researchers hope to elucidate its pathogenicity.
"We're hoping that … we will be able to figure out the phenotype that's associated with that variant and add some clarity to ClinVar and other databases as we start to deposit our data," Murray said. "That's in the works, we don't have our shining examples yet, but we know that we will be able to do that."
Another example is a variant of unknown significance in one of the BRCA genes, which they found in more individuals in the MyCode cohort than the number of cases with this variant currently reported in ClinVar and other databases. Through clinical phenotype and segregation information, they hope to better understand the role of this variant.
"I think we'll continue to find examples like this in our data," Murray said, and because they have not only patients' EHRs but also the opportunity to reengage with them, "we think we're in a position to really help to clarify the interpretation of some of these variants."
For pathogenic or likely pathogenic variants that were returned to participants, the project may help shed light on their penetrance, based on individuals who carry such variants but do not show signs of the disease.
Last month, researchers led by Mount Sinai School of Medicine published a study that looked for such cases in large datasets of genomic and phenotypic information, a pilot for a so-called "Resilience Project", but they were unable to recontact the individuals they identified to verify their results.
The Geisinger researchers, on the other hand, plan to study cases of apparent non-penetrance in more detail. "We can bring them in and phenotype them in a much deeper way related to whatever we find, or survey them, or invite family members," Murray said.
For all three conditions they have been returning results for so far, they have come across individuals who, according to their EHRs, have not been diagnosed with the disease, or have not developed any symptoms. The idea is to recontact them to confirm whether they indeed do not have the condition, or whether symptoms had been overlooked.
"We think that we'll have lots of individuals who are non-penetrant who will provide opportunities to better understand the mechanisms for their non-penetrance," Murray said.
While the Mount Sinai team has been looking at rare Mendelian diseases, the Geisinger study is focusing on less rare conditions, "but I think it's the same concept," he said. "They are trying to find examples of genetic risk and no phenotype, or mild phenotype. And we're finding that, and lots of it, in our data."