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Children's Mercy Hospital Explores Rapid WGS for Newborn Screening, Disease Diagnosis

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This is the third 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 Children's Mercy Hospital in Kansas City are embarking on a study of the value of rapid whole-genome sequencing in newborns, both for diagnosing sick babies and for routine newborn screening.

Earlier this month, the team, led by Stephen Kingsmore, director of the Center for Pediatric Genomic Medicine at Children's Mercy, received more than $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 that received a total of $25 million (CSN 9/4/2013).

According to John Lantos, director of the Bioethics Center at Children's Mercy and a study investigator, the goal of the project is twofold: to test whether whole-genome sequencing for routine newborn screening works better than the standard approach – a mass spectrometry-based blood test that looks for approximately 60 metabolic diseases – and to see whether whole-genome sequencing performs better than the standard of care – tests for individual diseases – to diagnose babies with unknown genetic syndromes in the neonatal intensive care unit.

"There is a big question about whether this sort of testing is going to be perceived by clinicians as clinically useful, or perceived by parents as beneficial," Lantos said. "How many babies that get such a test will have their treatment altered in a way that's beneficial, how many will the test be simply irrelevant for, and in how many will it actually create the possibility, or the reality, of harmful interventions – that's what we are going to be looking at."

The goal is to recruit 1,000 newborns over the next five years. All participants will receive conventional newborn screening, and either half or three quarters – including both healthy and sick children – will undergo whole-genome sequencing, using the rapid STAT-Seq test that Kingsmore's group has been pioneering, publishing a proof-of-concept study last year (CSN 10/3/2012).

The plan is to use the STAT-Seq test, which runs on two Illumina HiSeq 2500 sequencers at Children's Mercy and has a time-to-result of about 50 hours, not including Sanger confirmation, to analyze approximately 600 genes associated with autosomal recessive diseases.

So far, the researchers have used STAT-Seq in 15 newborns with unknown genetic disorders and have been able to find the genetic disease cause for 10 of them, according to Kingsmore.

The conventional screening test – an enhanced test developed by PerkinElmer – will look for 60 metabolic diseases. Not all of these can be picked up by whole-genome sequencing at this point because the underlying genes are not known yet, Lantos noted, though this will likely change in the future.

Sick babies in the NICU control group will receive diagnostic tests for individual diseases, based on their doctors' best guesses.

By restricting the analysis of the whole-genome data to only 600 genes, the researchers will avoid incidental findings. "We won't look at the other 19,000 genes at all," said Lantos, who is also a professor of pediatrics at the University of Missouri. "We won't be looking at BRCA1, genes associated with Alzheimer's, all the things that have been the traditional concern of debates about incidental findings."

The scientists have not decided yet, though, whether they will follow the recommendations of the American College of Medical Genetics and Genomics to include results for 57 genes related to 24 disorders, among them adult-onset conditions. "We don't like those recommendations and would prefer not to do that, although we're still trying to figure out whether it would be better not to do it or whether it would be better to study them," Lantos said, adding that they might let parents decide whether or not to receive these findings.

The standard for genetic testing in children has been to test only for diseases affecting the child's health, he explained, and to let patients decide as adults whether they want to be tested for other conditions. "Testing newborns for, let's say, Alzheimer's disease genes takes away their right to decide whether they want to know that information or not," he said.

Also, the ACMG recommendations are at odds with recommendations by the American Academy of Pediatrics, he said, which advocates testing children only for conditions that are not adult-onset, "so we're sort of caught between professional organizations' recommendations," he said.

In the past, Lantos said, newborn screening has turned out to be beneficial for managing some diseases but not others. "We're wondering, where is this new genetic test that has 600 different [genes] going to fall on this spectrum?"

For cystic fibrosis, for example, a clinical trial showed that babies screened at birth fared better than babies who were diagnosed later in life.

A newborn screening test for Krabbe disease, a lysosomal storage disorder, on the other hand, resulted in positive results for children that were asymptomatic, raising anxiety in their parents and leading, in some cases, to unnecessary treatments, Lantos said.

Besides looking at diagnoses made, the scientists will also study doctors' and parents' responses to the test results, comparing at least 100 who received whole-genome sequencing and 100 who obtained conventional diagnostic testing. The researchers will ask them immediately after receiving the results, and again after a year, whether they found the test to be useful, harmful, or irrelevant. In addition, they will correlate their answers to whether the test result changed the treatment or management of the child, and they will correlate parents' responses to their knowledge of genetics, health literacy, anxiety levels, religiosity, and other factors.

"One thing people have found in the past is that getting genetic testing increases anxiety and depression in the short term, but most people, in spite of that, say they're glad they got tested and will do it again," Lantos said.

The Children's Mercy researchers will also collaborate with the other three centers that received NIH funding under the newborn sequencing program – Brigham and Women's Hospital and Boston Children's Hospital; the University of California, San Francisco; and the University of North Carolina at Chapel Hill. These groups "are all coming to it from slightly different angles, but there is a lot of overlap, so to the extent that we can come up with standard approaches, we'll be able to pool data and get a lot more babies enrolled in comparable ways," Lantos said.

On the technical side, Kingsmore's group is working on reducing the turnaround time, or time-to-result, of the STAT-Seq test from 50 hours to 24 hours and will present initial results on this at the American Society of Human Genetics annual meeting next month.

That turnaround time does not include Sanger confirmation sequencing, which typically takes a week, Kingsmore said, adding that CLIA certification of the STAT-Seq test still has "some way to go."

In addition, he and his colleagues are focusing on improving the test's diagnostic sensitivity, both by using longer reads and different insert sizes, and by optimizing the analysis, including alignment tools, variant calling algorithms, and tools to detect mutations other than single-nucleotide changes.

Further, they are seeking to improve the cost-effectiveness of the test by trying to identify patients who will benefit the most, and by figuring out who needs emergency versus routine genome testing.

As of last year, the STAT-Seq test cost about $13,500, but costs have likely dropped since then, Kingsmore said, although his group has not done a careful analysis yet.

In the long run, improved screening technologies will likely provide not only better disease diagnoses but also information about disease risks and an individual's response to drugs, Lantos said, and the newborn sequencing study will help explore those avenues. "Every medical innovation is a double-edged sword, there is always a balance of risks and benefits," he said. "The trick is to be exquisitely attentive to potential risks so that you don't let them outweigh the benefits as you go."

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