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UNC Planning Randomized Study of Whole-Exome Sequencing in 400 Newborns under New NHGRI Grant

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This is the fourth in a series of profiles of centers awarded grants this year by the NIH under the Genomic Sequencing and Newborn Screening Disorders research program.

Researchers at the University of North Carolina will embark next year on a study of the value of whole-exome sequencing for routine newborn screening, splitting a cohort of 400 babies into two groups: one, a set of infants from healthy pregnancies, and the other, a group with either a positive result after receiving current standard newborn screening or a suspected genetic disorder.

Last month, the team, led by UNC's Jonathan Berg and Cynthia Powell, received an initial $5 million in grant funding over five years from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Human Genome Research Institute for the project, one of four separate efforts that are slated to received a total of $25 million to explore the potential for genome sequencing to improve newborn healthcare (CSN 9/4/2013).

UNC was also a recipient of NHGRI funding as one of six grantees under the agency's Clinical Sequencing Exploratory Research program for a study evaluating whole-exome sequencing in clinical practice (CSN 1/25/2012). Berg, who is a leader on both projects, told CSN this week that the new infant sequencing effort will be informed by the team's experience thus far in the CSER study.

According to Berg, the UNC infant project has two main goals: to evaluate whether whole-genome sequencing can add value to the tests currently used in routine newborn screening and to tease out how the process of receiving sequencing results for a child impacts families over time and can be best optimized both practically and ethically.

"When the RFA came out for this, we were all very excited about it and started talking about how different sequencing in newborn screening is than it is in the diagnostic setting. We actually almost convinced ourselves that it was not a really good idea to start doing exome sequencing in babies, mostly because when you are looking at a newborn, almost everything is an incidental finding from a conceptual standpoint," Berg said.

"But we regrouped and decided that it is really important to be involved in studying this, and that we had a good model for how to organize genomic findings."

In the study, Berg said he and his colleagues will adapt a genome "binning" strategy they developed in the CSER project, changing the design so that the contents of different bins are suited specifically for decision making in the newborn screening space.

Overall, the group plans to sequence the exomes of 400 infants. As part of the study, this cohort will be randomized. Half will be given only some genomic results, and the other half will be offered the option to receive additional information if they want it.

The group plans to have a first "bin," Berg explained, that will consist of findings that are medically actionable in the period of infancy and early-childhood.

"Those would potentially be what we would add to a standard newborn screen— conditions we feel have similar characteristics to what are currently screened for, where you could potentially intervene to improve outcomes."

A second category will include findings that are also medically actionable, but not until adulthood. Exactly which findings will make the cutoffs to be in both of these bins is still something the team is working on deciding, Berg said.

But the plan is for all parents to be given results that fall within the newborn screening bin, and then be randomized either to a control arm that gets no additional genomic information, or to an arm where they can decide what additional categories they would like to learn.

"The options will be split into categories that hopefully allow them to make salient decisions," Berg said. "And we will study how useful that type of categorization is, what types of information people choose to learn or not, and what is behind those decisions."

The category of genomic information the group will not return to any participants in the study will be larger than it is in UNC's CSER project.

"There is certainly information that doesn’t have any clinical significance — mutations in genes that have not shown to have anything to do with human disease — that we consider to make up a third bin," Berg said. "But in the newborn study we will be modifying that category to also include other information that parents will not have access to."

Though the team has not fully designed the perimeter for this bin yet, Berg said it will include things like mutations associated with untreatable, adult-onset neurodegenerative diseases.

"In our other study, if you are an adult, you can choose to learn these things about yourself, but we feel that this is information the child has to have an agency in deciding about for themselves. Doing the hard work of deciding which conditions meet criteria to go into that category will be very interesting and important," Berg said.

Berg said that UNC is currently using Agilent exome-capture reagents, but the group also plans to adopt a "Medical Exome" sequencing strategy — being developed by Emory University's Madhuri Hegde with colleagues at the Children's Hospital of Philadelphia and Harvard's Laboratory of Molecular Medicine — designed to ensure complete coverage of around 5,000 medically relevant genes (CSN 5/1/2013) as part of the newborn sequencing study.

All samples will be sequenced in house at UNC's High Throughput Sequencing Facility, Berg said, and any variants the group plans to report to patients will also be independently verified in the university hospital's CLIA lab.

According to Berg, the study's 400 participants will be split down the middle, with half being presumably healthy babies recruited prenatally among couples with low-risk pregnancies, and the other half being either infants who have a positive test result for some condition after standard biochemical newborn screening, or children with a disorder that the group believes could have benefitted from early diagnosis using whole-exome sequencing.

"We decided that one thing we wanted to really tackle was the question of how next-gen sequencing can be used as an adjunct — to amplify or augment the information you get from a standard biochemical newborn screen," Berg said. "We want to look to see if DNA sequencing data helps to inform interpretation of a biochemical finding and guide [subsequent] follow up."

"If, for example sequencing could show that an elevated phenylalanine level does not indicate PKU, but rather hyperphenylalaninemia, that could be a potential benefit to sequencing at birth," he said. "And also for children with rare genetic disorders that you can't screen for with current biochemical panels, things like disorders of copper metabolism and mitochondrial disorders, we'd like to see if sequencing could have diagnosed them."

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