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Early Adopters of Clinical Sequencing Warn It's Not a One-Size-Fits All Approach

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By Monica Heger

While an increasing number of labs are adopting clinical sequencing protocols, early adopters who spoke at a recent conference noted that the lack of standards in the field requires a case-by-case approach to resolving issues that may arise.

At last week's Future of Genomic Medicine conference at Scripps Translational Science Institute in San Diego, a number of researchers presented their protocols for introducing clinical sequencing, highlighting the different tactics that each institute is taking in terms of what patients to sequence, what results to return, what sequencing strategy to use, and the challenges of correlating sequence findings with phenotype data.

During a panel discussion, a number of researchers discussed the benefits and challenges of different types of clinical sequencing protocols, highlighting the wide variety that is currently offered and the fact that while sequencing is increasingly used in a clinical setting, there is not yet a standard for how it should be done.

Sequence First, Ask Questions Later

What patients should be eligible for sequencing — and when those patients should be sequenced — was one major point of discussion, and researchers do not yet have a consensus on the answers to these questions.

Stan Nelson, professor of human genetics at the University of California, Los Angeles, who is heading up the university's recently launched clinical exome sequencing service (see story, this issue), has taken a permissive view on who should be sequenced.

While UCLA's exome sequencing service is geared toward pediatric patients whose disorder is likely to be monogenic, Nelson's philosophy is to "sequence first, ask questions later," meaning that he does not think that patients should have to go through a diagnostic odyssey before becoming eligible for exome sequencing.

"If you think it's genetic, at the end of the day, the child deserves exome sequencing at the very least," he said during a presentation at last week's conference.

On the opposite end of the spectrum is the tactic that the Medical College of Wisconsin and Children's Hospital of Wisconsin have adopted with their whole-genome sequencing pipeline.

Under their protocol, physicians must have exhausted all other options before the child will be approved for whole-genome sequencing.

"This is a diagnostic of last resort," said Howard Jacob, director of the Human and Molecular Genetics Center at MCW. Additionally, sequencing must be "likely to obtain a genetic etiology" of the child's disorder.

The MCW team has a comprehensive process by which patients are selected for sequencing. First, the patient must be nominated by two physicians. The case is then taken to a board comprised of ethicists, bioinformaticians, physicians, and genetic counselors. Both parents must agree on the sequencing since data will be collected from each of them as well.

Of 60 cases that have been brought before the board, 18 have been approved, he said. Of the ones that were denied, there are several cases where the physician sent the cases out for commercially available exome sequencing services. "That's an interesting lesson" that suggests the team should possibly approve more patients, Jacob said.

However, he noted that the MCW team has stringent requirements about what patients it will accept for sequencing because it wants to maximize the benefits of performing the whole-genome sequencing, since so much information could potentially be uncovered about the patient and family members.

Even still, he said, not every case has been a success story. For instance, in one case the MCW team has been analyzing a patient's genome since July, unable to find the causal variant.

“When do you stop?” he asked. “We found some likely genes, but nothing definitive."

Return of Results

While Jacob's team is on the more conservative side when it comes to which patients to sequence, it is more permissive about what types of results it will return.

By law in Wisconsin, the team is required to return results that inform the child's primary diagnosis and also any actionable results that are predictive of childhood-onset diseases. After that, parents have an array of choices, ranging from receiving no incidental findings, to receiving non-actionable incidental findings about childhood diseases, actionable findings related to adult-onset diseases, or non-actionable findings related to adult-onset diseases.

Of the 13 families that have gone through the process, he said, one family decided to opt out of the sequencing altogether, but only one family chose to not receive any incidental findings. About half opted to receive all incidental findings, even those that were not actionable.

Restricting information to actionable data presumes that actionable data is beneficial, "but that's not necessarily true," he said. "Actionability is subjective" and "does not respect subject autonomy," he said.

During the panel discussion, others questioned the choice to return information about adult-onset disorders in children, saying that it took away the child's right to know or not know about their own genomes.

Jacob said that the MCW group has had "a lot of internal debate" about the subject, but ultimately decided that parents already make so many decisions for their children that have even greater impact on their lives, that it would be presumptuous to decide for the parents whether to return the information. Ultimately, "it's their genome, it's their family," he said. "We feel more comfortable with parent autonomy and working with them on this then we do about not giving them the option," he added.

At the other end of the spectrum is the protocol employed by Nelson's UCLA team, which only reports back variants likely to be causal of the patient's disorder. The remainder of the data is kept in a database, affiliated with, but not attached to, the patient's medical record, he said. For patients who do not receive a diagnosis, the data can be re-accessed as new information becomes available, and researchers can also mine the data in conjunction with other genomic data to try to find disease-related variants.

"A lot of the data will ultimately be interpretable," said Nelson, but not necessarily at the time of the sequencing.

One of the reasons the UCLA team returns only data relevant for the patient's disease is that it is considered a diagnostic test, not an exploratory study, and Nelson said there would be a danger of over-interpretation if additional information was considered. For instance, he said, exome sequencing uncovers around 200 variants per person that are predicted to be protein damaging. But not all of those will cause disease, even if they are in disease-related genes, and "we will get ourselves into trouble by over-interpreting that data."

"We can't put our arms around what all those variants mean," he added.

Lynn Jorde, a professor of human genetics at the University of Utah and a co-author of the whole-genome sequencing study that identified the cause of Miller syndrome, agreed that "overcoming the analytical bottleneck" is still one of the biggest challenges of using next-gen sequencing in the clinic.

He said it is important to "emphasize how challenging these studies still are" when discussing them with patients.

Correlating Phenotype with Sequence Data

While the groups doing clinical sequencing are all taking slightly different approaches, one thing they agree on is the challenge of correlating a patient's initial diagnosis with the actual sequencing results.

Joe Gleeson, a professor of neurogenetics at the University of California, San Diego, said that in his exome sequencing research studies of consanguineous families with severe neurodevelopmental disorders, he has found that patients are frequently either misdiagnosed or not fully diagnosed.

In about 10 percent of the cases he has sequenced, "the initial diagnosis did not match the genetic diagnosis," he said. In those cases, his team went back and confirmed that the patient did in fact have clinical features indicative of the genetic finding that had either been missed or under emphasized. "Patients weren't grossly misdiagnosed, just partially misdiagnosed," he said.

Because he is doing sequencing in a research setting, the results are not used to guide patient care, but he does have institutional board review approval to return disease-relevant findings either back to the physician who can then validate the finding in a CLIA environment or directly to the family, whichever the family prefers.

He said that in his exome sequencing studies, it has become clear that "making a correct diagnosis will be a first step toward future clinical trials."

One of the problems with much of the clinical information available on the patients is that the electronic medical records cannot be easily customized, and instead are very much "drag and drop." Electronic records, while accessible, "have lost the richness" of dictated or written reports, he said.

UCLA's Nelson said this difficulty of correlating phenotype and genotype is one of the reasons he thinks sequencing should be done early in the diagnostic process — after taking a family history. "If it's clearly a rare trait, our ability to phenotype it well is [limited]," he said, making it challenging to choose the correct genetic test.


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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