Researchers at the Montreal Heart Institute are working with GnuBio to develop a cost-effective test to screen patients for risk of sudden cardiac death using the company's microfluidics-based sequencing platform.
MHI is planning to use a beta version of the GnuBio desktop DNA sequencing system, which the company expects to release in the second quarter of this year, to validate a panel of genes associated with SCD-causing cardiac abnormalities. The institute hopes to create a lab-developed test affordable enough to be used in routine screening of athletes and others considered at risk, Michael Phillips, director of MHI's molecular diagnostic laboratory, told PGx Reporter.
"If the GnuBio box can do what we think it can do, this becomes one of the first opportunities to do cost-effective, preventative testing in the athlete population — [maybe a situation where] we test everyone coming into soccer camp or the [National Football League]," said Phillips, who has worked closely with GnuBio previously and is a member of the company's scientific advisory board.
While it is hard to predict an exact cost per sample since the GnuBio machine hasn't been released yet, Phillips said he expects the overall cost per patient to be "substantially less" than approaches using Sanger sequencing or other next-generation sequencing platforms. "It will be in the hundreds [of dollars] versus the thousands," he said.
John Boyce, GnuBio's president and CEO, told PGx Reporter that the sequencer will cost about $50,000 and that the company expects total per-patient costs to settle between $150 and $200 at 100x coverage.
According to Phillips, doctors examining heart rhythm abnormalities that can cause SCD have begun to routinely recommend that patients with these changes undergo genetic testing. "This is almost becoming standard of care," he said. "The clinic basically sends all these patients to us to check for whether they have inherited mutations."
While genetic testing using Sanger sequencing and arrays has become more common, routine clinical screening using sequencing has not yet been practical due to the complexity of sample preparation and the requirement that a large number of patients be tested for a sequencing-based test to be cost effective, Phillips explained.
SCD, a condition where the heart unexpectedly stops beating, can be the result of a number of physical occurrences. Cardiac channelopathies cause the heart to miss-time its electrical signals so that the muscle vacillates without pumping blood through the body. Hypertrophic and dilated cardiomypathy, two types of thickening of the heart muscle, are even more prevalent issues that can lead to SCD, Phillips said.
If a patient is known to be at risk for SCD, an implanted defibrillator can help restart the heart if such an event occurs. But the tragedy of the disease is that it strikes those who appear healthy, causing unexpected and sudden death. Usually, "unless you are undergoing testing for some other reason, a young healthy person isn't likely to have a CT scan showing the heart dilated" or any evidence of channelopathies, and so there is no way to know who to treat, said Phillips.
With growing knowledge of mutations associated with these disorders, two groups have recently published recommendations supporting the use of genetic testing to screen patients.
One set of recommendations, by the Canadian Cardiovascular Society and Canadian Heart Rhythm Society, was published last year in the Canadian Journal of Cardiology. Another, by the Heart Rhythm Society and the European Heart Rhythm Association, was published in the journal EP Europace. Both groups recommend testing for patients with phenotypic presentations related to channelopathies and some cardiomyopathies, though they differ on specifics related to the recommended targets and comprehensiveness of testing.
SCD, while relatively rare, is common enough and devastating enough that routine testing has a lot of support, according to Phillips, who characterized the disorder as a particularly good target for a sequencing-based test because of the large number of mutations that are associated with SCD.
"These are not common variants," he said. "They are what we call 'personal mutations.' So the only way to really screen for this is de novo sequencing," he said.
However, current sequencing technologies are not an especially good fit for a rarer disease like SCD — which strikes about 1 in 44,000 student athletes a year, according to Phillips — because physicians won't find themselves clinically collecting the large numbers of samples required for most sequencing systems to be affordable.
Because of this, he said he sees the GnuBio technology as bridging a gap between sequencing capability and the needs of clinical molecular diagnostics.
"I see the GnuBio as one of the first desktop systems that can really start to be clinical," he said.
Boyce also stressed the company's advantage in this respect.
"With other high-throughput sequencing companies, they go to a clinician and say, 'It's two dollars to run your 20-gene panel,' but it's two dollars only once you sequence 2,000 or 3,000 patients," he said. "What we wanted to do was make something scalable where the cost per patient remains fixed.
"In the real world, you get five samples in a day, or seven at a time maybe, or even one sample [and] you need to get your answer within two hours and get that back to the patient," he said.
Phillips said his team at MHI plans to build a "broad-based panel" that encompasses "most of the known genes [for SCD risk] and the ones that are currently on the cusp."
The group will work with other institutions, he said, to make sure the panel has the right content. Beyond that he did not specify how many genes his group may hope to add to those markers that are already solidly associated with SCD, or how many the panel is likely to interrogate in total.
Phillips expects that an affordable genetic test for SCD will be welcomed by the community of physicians who treat those at risk for the disorder. MHI has already been routinely testing patients with channelopathies and cardiomyopathies for genetic mutations. A GnuBio sequencing test would offer a more comprehensive look, he said.
While there has been resistance among some clinicians to adopt genetic tests for use in drug monitoring or stratification for patients with other cardiovascular diseases, Phillips observed that the case of SCD is much more straightforward.
"Electrophysiologists understand this stuff quite well and it already guides their decision making," he noted. "If we can demonstrate that we can build a cost-effective clinical panel and actually put it in the clinic here, I don’t see many barriers to entry."
After MHI develops this panel as an LDT, it will most likely be up to GnuBio to further develop the test for use in other healthcare settings. "The opportunity for us," Phillips said, "is to build this for ourselves, but also working with GnuBio, we'll pass that back to them and it becomes something that can be used at the point of care at other hospitals." According to Boyce, at least 20 labs have expressed interest in using the SCD panel.
Pathological post-mortem testing could also be a potential application for the panel. If someone dies, Phillips said, you can't use electrocardiography to establish whether they suffered a cardiomyopathy or channelopathy. "But sequencing could give you insight into the cause of death."
Phillips believes there is also great potential for GnuBio panels to screen patients for a range of other diseases, especially in oncology and infectious disease settings.
GnuBio has active partnerships with "at least eight" other groups to develop diagnostic panels across "oncology, pathogen detection, and cardiovascular and metabolic disease," according to Boyce. The company has an oncology panel in development in partnership with City of Hope cancer center, which they plan to eventually offer as an LDT on the GnuBio system. He declined to name other specific groups the company is working with.
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