NEW YORK (GenomeWeb) – Two years after the Rady Children's Institute for Genomic Medicine in San Diego came into being, and a year after it hired clinical genomicist Stephen Kingsmore as its first president and CEO, the institute has launched a rapid genome sequencing test for critically ill newborns.
In addition, the institute is preparing to get several clinical trials and programs underway that will examine the benefits of clinical genome sequencing, and has formed a consortium with five other children's hospitals to advance genomic medicine in pediatrics.
The institute, previously known as the Rady Pediatric Genomics and Systems Medicine Institute, was founded in 2014 with a $120 million gift from Ernest and Evelyn Rady and $40 million in committed funding from Rady Children's Hospital.
A year ago, the institute hired Stephen Kingsmore from Children's Mercy in Kansas City, where he had pioneered fast genome sequencing for diagnosing newborns with suspected genetic diseases, a test called STAT-seq, under the National Institutes of Health's Newborn Sequencing in Genome Medicine and Public Health (NSIGHT) program.
So far, the institute has hired 22 individuals in various positions, including program managers, genetic counselors, technical personnel, and postdocs, Kingsmore told GenomeWeb last week, who previously worked at Baylor College of Medicine, the Medical College of Wisconsin, Illumina, Life Technologies, and other places.
Kingsmore has also transferred the INSIGHT grant to Rady Children's, which over the last couple of months has enrolled 27 families and their newborns into the project and completed genome analysis for 24 of them.
The institute recently opened its clinical genome center, which is currently equipped with an Illumina HiSeq 4000 and two HiSeqs 2500. The center is in the midst of validating its protocols for rapid genome sequencing and hopes to become CLIA-certified and CAP-accredited next year. At that point, it will commence clinical production sequencing, Kingsmore said, and might add sequencing instrumentation depending on demand.
In the meantime, most of the genome sequencing is outsourced to Envision Genomics, a recent spinout from the HudsonAlpha Institute for Biotechnology in Alabama. However, in two cases, which were too urgent to send out the samples, the Rady team sequenced the newborns' genomes in house, Kingsmore said, returning preliminary test results within 68 hours in one case. That child had already been on the way to emergency surgery, which was canceled based on the test result, he said.
Overall, of the 24 families whose children underwent rapid genome testing, 13, or 54 percent, received a diagnosis. This is in line with the 57 percent diagnostic rate that Kingsmore's group at Children's Mercy previously published on their first 35 cases.
Seven of the newborns who obtained a diagnosis, or 29 percent of all cases, had a change in their clinical management that was prompted by the test result, Kingsmore said. In several cases, this meant treatment with a different drug — for example, one child with seizures switched to another anti-epileptic medication, and another child with a metabolic disorder was started on a specific treatment for that. In another case — a child that had been in the neonatal intensive care unit for seven months — the diagnosis led to the decision to proceed to palliative care.
Several differences exist between the original rapid genome test that Kingsmore's team established at Children's Mercy and the one it just implemented at Rady Children's.
On the technical side, the Kansas City lab used a modified HiSeq 2500 with shortened cycle times that increased the overall speed of the assay to 26 hours. For the new San Diego lab, the team is in discussions with Illumina about developing a rapid run mode for the HiSeq 4000 instead, which would allow them to run a parent-child trio on a single flow cell. "That would probably be ideal for acutely ill newborns," Kingsmore said.
Regarding data analysis, Rady Children's works with DNAnexus, using its cloud-based method for transferring data, and has a collaboration with Edico Genome, utilizing its Dragen platform for read alignment and variant calling. The institute recently hired Narayanan Veeraraghavan as its director of informatics, who came from Baylor College of Medicine's Human Genome Sequencing Center, and the system he built bears some similarities to Baylor's, Kingsmore said.
For variant interpretation, Rady Children's works with the Omicia Opal system and Ingenuity Systems' software, whereas at Children's Mercy, the group was using a homegrown system called VIKING. "When we started in Kansas City, there really was no commercial product that fit that need," Kingsmore recalled. "Now there are several."
One striking difference between the two places is how often families consent to genome sequencing for their newborns: While the consent rate was about 50 percent at Children's Mercy, it has been close to 95 percent at Rady Children's.
The reason for that warrants further research, Kingsmore said, but one factor might be that neonatologists at Rady are more involved in the testing process and encourage families to a greater degree. "I feel like probably we have a slightly different team structure where the neonatologists are on the team to a greater degree than is possible at other places," he said.
Another possible reason might be that residents of San Diego are just more familiar with what a genome is, he suggested, because genomics companies, like Illumina, "are common employers in San Diego."
Kingsmore has also been wrapping up ongoing work at Children's Mercy, for example a randomized controlled study that compared families with newborns in the NICU who received conventional diagnostic testing —including microarrays, single-gene tests, and next-gen sequencing panels — with children who received conventional testing plus rapid diagnostic genome sequencing. To his knowledge, the study, which involved 65 families, is the first to compare genome-based diagnostics with standard approaches, and "it did show a significant difference [in the number of diagnoses] in the group that was getting genomes," he said.
Overall, 41 percent of those undergoing rapid genome sequencing received a diagnosis within 28 days, whereas that number was significantly smaller in those who did not, Kingsmore said. The group plans to publish the results in the near future, he added.
The Rady team is currently preparing to launch a clinical trial early next year that will compare the merits of clinical exome and genome sequencing in the neonatal and pediatric intensive care unit. "There have been lots of opinions in the community about which is best," Kingsmore said. "I think it's time to do a randomized controlled study and compare them head to head."
In addition, the institute is implementing a number of other programs. One is in the area of autism and intellectual disability, where the Rady team plans to enroll patients who will receive genome sequencing as part of their initial workup in order to look for structural variations as well as nucleotide variants that may help to explain their condition. "We're keen to understand whether genomes can be used to stratify patients at first diagnosis of one of these disorders," Kingsmore explained, noting that the genome sequencing will be conducted under a research protocol. "It's an added research test, and we want to see what its benefit is for patient management."
Another program, in neuro-oncology, has already enrolled its first patient. For this, patients will receive matched tumor/normal genome and transcriptome sequencing.
While the current programs are aimed at patients treated at Rady Children's Hospital, the plan is to expand to the University of California San Diego Medical Center next year, Kingsmore said, given that many Rady pediatricians are affiliated with UCSD.
Rady Children's Hospital is also one of six pediatric hospitals that are part of the Sanford Children's Genomic Medicine Consortium, which was announced in September and aims to integrate genomic medicine into pediatric care. As part of that, Rady Children's plans to introduce rapid genome sequencing to the NICUs of the other hospitals, Kingsmore said.