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Whole genome sequencing procedure

Whole genome sequencing procedure -

Scientists can recreate a person's whole genetic material by aligning all the short fragments of DNA sequence data that overlap one another. The final sequence can be used by researchers to find disorders or other irregularities, which can then be used by doctors and clinicians to provide health care accordingly.

Photo by Nat Chow

Even without any complications, having a child can be a stressful time for couples. For individuals with a family history of genetic disorders, the uncertainty and stress might even be higher.

Since the 1970s, genetic testing has helped to inform such families of the risks of passing on certain inheritable disorders to their children. Now, with recent advances in genetic sequencing technology, a team of UW researchers is leading an exploratory study to determine the logistics, benefits, and concerns of expanding the role of more comprehensive genetic testing for couples prior to conception.

Genetic testing or sequencing is used to determine whether a person carries a copy of a mutated gene that, when present in two copies, will cause a genetic disorder. However, up to now, such “carrier tests” have been conducted on a disorder-by-disorder basis to reduce costs and are usually done during pregnancy.

“All things being equal, we think it’s always better to do [genetic sequencing tests] before [conception] than during pregnancy, because you don’t have the context of an ongoing pregnancy in making difficult decisions,” said Dr. Benjamin Wilfond, UW pediatric bioethicist at the Seattle Children’s Research Institute.

Wilfond is one of the five UW scientists — along with Dr. Gail Jarvik, Dr. Wylie Burke, Dr. Deborah Nickerson, and Dr. Peter Tarczy-Hornoch — with a leading role in this study. They explored the implementation of whole genome sequencing to pre-conception carrier testing.

According to Wilfond, the plummeting cost of genetic sequencing over the past decade has made sequencing an individual’s entire genome or DNA sequence economically feasible. With this data, scientists can simultaneously look for mutated copies of many genes known to cause a wide variety of genetic disorders while also screening for genes that increase the risk for other maladies.

Wilfond added that while whole genome sequencing could be helpful in the clinical setting by providing physicians and a child’s parents with a great deal of information, the effects of this information — as well as the best way to present it — is wholly unexplored.

“We really don’t quite know how helpful or how problematic this [information] can be,” Wilfond said.

Jarvik, UW professor of medicine and genome sciences, said the information can be ambivalent.

“In the abstract, all information seems like a great thing. But when you actually have the information, it might not be as fabulous as you thought,” Jarvik said.

This research is funded through the Clinical Sequencing Exploratory Research (CSER) program grants, which will be awarded by the National Institute of Health (NIH) over the next four years. The study will enroll members of the Kaiser Permanente health plan in Oregon and Washington that have already requested a preconception genetic test through their health care provider.

Once enrolled, these individuals will be randomly assigned to two groups. Participants will only receive results from tests they requested, while participants from the other group will receive their requested tests along with whole genome sequencing results. The second group serves as the control group to better understand how patients react to the process of whole genome sequencing and their results from it.

Those in the first group can choose to receive results from different categories of genetic conditions with varying degrees of severity and lifestyle impacts. Examples of genetic conditions range from Tay-Sachs disease, a life-threatening disease of the nervous system, to developmental disorders.

Among the test categories with less severe and immediate implications are pharmacogenes, a category of genes that research has shown to impact an individual’s response to drugs.

Nickerson, the researcher overseeing the analysis and annotation of the genomic data, is particularly interested in how participants will respond to the results obtained from sequencing the pharmacogenes. She believes that determining possibly adverse reactions to specific drugs will greatly assist doctors in providing the highest quality and most cost-effective care to patients.

In addition, participants can choose to have “incidental findings” — genetic risk factors that could be relevant to their personal well-being — analyzed and returned as well.

“We call these genes ‘actionable’ because there’s something that can be done. These risks could be fatal if not followed on and treated,” Jarvik said.

While Wilfond hypothesizes that participants will likely request for all the available options, he thinks their response to the categories with less severe conditions will be interesting.

“We want to know how the participants view the different levels of risks for these conditions,” he said. “What do they think is important?”

Sequencing will be conducted by Illumina, Inc., a company based in San Diego, Calif., and then the raw data will be given to the UW team for analysis and interpretation. The UW team is currently in the process of finalizing which genetic disorders will be included in the study.

Only the UW researchers’ interpretation of the sequencing data will be returned to the couples and put into their medical records. Genetic counselors will be assigned to thoroughly explain the results and their implications.

In order for health care providers outside the study to properly utilize these results and tailor their care accordingly, clinical decision support will also be added to the record. 

“They need information on what to do with these results,” Jarvik said. “For example, writing in ‘Don’t put this patient on this drug’ or ‘If you do, put them on a lower dose.’”

Jarvik emphasizes the importance of finding the balance in the amount of information released.

“We want to learn what information is useful for people,” she said. “When does it become information overload and just ends up worrying people?” 

Throughout the study, the participants as well as the health care professionals involved will be interviewed and given surveys to determine not only the impact of using whole genome sequencing over individual genetic tests, but also the additional support necessary for its implementation. 

“Hopefully this exploratory study will give us information to help us design other studies further down the road,” Wilfond said.

Wilfond feels that whole genome sequencing will eventually become the norm, replacing individual tests.

“I don’t know what the time frame for this would be though. I think there won’t be widespread adoption for a while for a wide variety of reasons,” Wilfond said.

Jarvik thinks the cost of whole genome sequencing makes it the better option in the long term.

“Considering that whole genome sequencing provides so much more information to look at, so many more variables to consider, if it’s fundamentally going to be the same price or a little bit more to do everything once, why not do everything in one step?” Jarvik said.

Despite the promise of whole genome sequencing, Jarvik cautioned to take this new technology with a grain of salt.

“I think for a lot of people that participate in studies like this, they expect that getting their entire genome sequence will tell them a lot. But really, for most people, this information is not changing their lives,” she said.

Reach contributing writer Kevin Kwong at development@dailyuw.com. Twitter: @DKdonkeykwong

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