B.C. Industry News

Vancouver Sun – Personal genomics: The test for everything

May 5, 2014

Part 1 in a series: When Genome BC’s Brad Popovich finally went looking for answers in his DNA, the result was not what he expected

By Randy Shore, Vancouver Sun May 5, 2014

In the course of his early research, the chief scientific officer of Genome BC routinely drew his own blood to compare with the DNA of people who were known to have disorders such as cystic fibrosis or spinal cerebral ataxia.

“I would draw blood weekly … and provide that to extract DNA,” said Brad Popovich. “The reason I was very comfortable doing that is that knew I didn’t have any one of those diseases. So, I was a good control.”

But over all those years, dating back to the late 1980s, Popovich never allowed his DNA to be tested for the APOE e4 gene. Having a single copy of the APOE e4 gene increases the carrier’s risk of late-onset Alzheimer’s disease. Having two copies — the e4e4 configuration — dramatically increases the risk yet again.

“I basically said to the lab: ‘I’m not a control for that test, I don’t want you ever to use me as a control for that test, because I don’t want to know and I don’t want you to know if I have that,’” he recalled.

“Both my maternal grandmother and my mom died of dementia and so there was a significant risk there,” said Popovich.

But when Popovich the son and grandson was faced with the opportunity to have his whole genome sequenced, Popovich the scientist had to come to terms with what the test would certainly reveal.

“When I did my whole genome, the biggest question was Alzheimer’s and is this going to show that I have a significantly increased risk,” he said. “Then, if so, what would I do with that information? We lived through what happened with my mom and I lived through it with my grandmother and if there is a higher probability of that happening to me … why not know that?”

Popovich’s decision, made with his wife Nicola, was made simpler because the two have no children. The presence of hereditary disease in his genome has no downstream impact, but a positive result for an Alzheimer’s-associated gene would have significantly changed both their lives.

“I’m at the point in my life where I just decided that if I had that information I actually could work with (it) in a constructive way, as constructive a way as not knowing,” he said. “I wanted to do this to become a consumer, to find out how you and I are going to access this information.”

Nicola said she was more concerned about the immediate emotional impact on Brad of “profound” findings from the process than the long-term consequences of any potential illness.

The $5,000 whole genome sequence and medical interpretation provided to Popovich by Illumina’s Understand Your Genome program did not find an e4e4 configuration, or even a single APOE e4. So, that was a relief.

“Had I turned out to be e4e4, I might have modified my lifestyle a little bit, maybe not work as many years as I thought I might, maybe I would decide to do other things,” he said.

“In retrospect, Brad’s experience was incredibly easy,” Nicola said. “We learned some helpful information, which has since been followed up with thoroughly by our GP.”

Unlike older genetic tests that could look only at specific parts of the genome, whole genome sequencing means that each time this tool is used to diagnose a patient’s particular form of cancer or estimate a person’s risk of Parkinson’s Disease, the information that comes back may indicate the presence of any of 20,000 known genetic markers for diseases.

Genome Graphic

Illumina returns each subject’s entire genome sequence on an iPad Mini and puts everyone through a one-day course on how to use the interpretive interface, along with a report on any variations in the sequence known to be associated with disease or dysfunction. Illumina also produces a report and a hard drive containing all the raw data to the physician. The entire process takes about three months from start to finish.

The diagnostic function of genetic testing can no longer be divorced from its powerful capabilities as a screening tool for 7,000 rare diseases, as well as risk factors for many common ailments. With whole genome sequencing, diagnostics and screening are not just connected, they are inseparable and unblinking.

Among the 3.4 million variations detected in Popovich’s sequence, about 1.3 million were present in the one to two per cent of his genetic sequence that provides instructions for biological processes. Most variations are the little differences that make Brad unique from other people. But some variations can indicate a predisposition to a disease ranging from highly predictive to slightly suspicious, or simply that the person is carrying the code and could pass it on to offspring.

The most surprising variation present in Brad’s genome was one associated with a mild predisposition for arrhythmia — an irregular heartbeat.

Markers for disease range from strongly predictive in a small handful of cases — some forms of breast cancer or Huntington’s Disease, for instance — to variations that are only faintly associated with a disease, requiring the confluence of many other mutations and environmental factors to have any likelihood of leading to illness.

“When I look at the underlying data, I agree with their assessment, this could be a disease-causing gene,” said Popovich. “It’s just as likely that it may not be.”

Just to be on the safe side, Popovich’s physician decided to record his heart activity for a 24-hour period, using a wearable heart monitor.

It was not the first time. Popovich wore a similar monitor years ago after a nurse taking his pulse thought she detected an arrhythmia.

“I had just drunk a pot of coffee, a typical Saturday morning for me … but she flagged it so my doctor put me on the monitor and did an exam and everything was fine,” he said. “Nothing ever came of it, but when I saw this (mutation) and my doctor saw it, we thought isn’t that interesting. She thought we should look at this again, so I’m in the midst of having it evaluated.”

The data from the heart monitor came back normal, but Popovich will still be taking his genome data to a cardiologist.

According to the data, Popovich is a carrier for hereditary hemochromatosis, a condition causing excessive iron absorption that would only affect his offspring if both parents contributed the gene.

“I already knew that from testing done in my old lab, but I’m also a carrier for something called Wilson’s Disease and another one called von Willebrand’s Disease,” he said. “Those are interesting, but they have no ramifications for me, unless I was to have children and my wife was also a carrier. Another copy (of the gene) has to be present.”

A powerful new tool

Illumina’s whole genome sequencing and interpretation requires the consent of a physician, who attests to a compelling medical reason for the procedure. Popovich’s family history of dementia was reason enough.

The company is a world leader in the manufacture of equipment for genetic analysis and has recently developed a clinical laboratory for consumer genomics and diagnostics, using its own advanced sequencers. The company also provides genetic screening for prospective parents, forensic services and agrigenomics to identify pathogens and guide animal breeding.

As the number of people who have their genome sequenced grows and the ability of the medical and scientific community to identify new markers and patterns of variations that are predictive of disease improves, the raw data set can be read again looking for new targets. The accuracy of the information won’t change, but our ability to interpret it will improve over time, possibly very quickly said Popovich.

“I’ve got my blueprint, and so anytime new information comes out I can interrogate my genome against that and find out if that is something that would be a risk factor for me,” he said. “It’s profoundly powerful.”

The number of genomes available for analysis is likely to grow very quickly in the next few years, each one helping to clarify the genetic variations associated with predisposition for all kinds of disease.

The first human genome that was fully sequenced cost $3 billion, just over a decade ago.

New sequencers generate a full genome for about $1,000 each. Popovich’s sequence including classes and medical interpretation cost $5,000. Illumina’s Understand Your Genome program is currently offered to industry, clinical, medical and academic professionals.

Benchtop sequencers used in research produce a raw data set for about $350. Direct-to-consumer genetic testing by 23andMe has recently dropped to US$99.

“The cost of DNA sequencing in just the past 10 years has gone down a million-fold,” said Popovich.

Test at birth?

Newborns in B.C. are routinely screened with a blood test for 23 rare, but treatable disorders, mainly metabolic and hormonal problems. Whole genome sequencing is potentially the test for everything and it already has the power to roughly gauge the risk of an individual for thousands of conditions.

“Is it theoretically possible to do whole genome sequencing on every newborn? Absolutely it is,” he said.

Such a test could be a revelation for early treatment, prevention and the use of targeted therapies, any or all of which would certainly deliver long-term savings to the health care system, said Popovich.

“Even in cases where you can’t do anything about (a condition), the fact that the family knows what’s wrong — let’s say with a child that is not developmentally the same as their peers — even if there is nothing you can do about it, it changes the dynamic for that family because they are no longer trying to figure out what’s wrong.” he said.

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