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Rady Children's Team Presents Genomic Medicine Management Tool at ASHG

NEW YORK – A Rady Children's Institute for Genomic Medicine-led team has developed an automated management guidance system for pediatric patients with rare genetic conditions who have been testing by clinical sequencing.

RCIGM President and CEO Stephen Kingsmore outlined the resource and rationale for it during a session on omics-based diagnostic approaches at the American Society of Human Genetics annual meeting, held virtually this week. He and his colleagues at RCIGM developed the online database — called Genome-to-Treatment (GTRx) — in collaboration with Illumina, Alexion Pharmaceuticals, the RPRD Diagnostics Lab, and several other research centers.

"The problem that we've been trying to overcome is the diagnostic odyssey, in particular focused on a specific patient population, which is infants and children in intensive care units with diseases of unknown etiology where a genetic condition is suspected," Kingsmore explained. "The historic problem has been that there are so many genetic diseases that pinpointing the right one in a timely manner has been impossible."

Kingsmore has been at the forefront of efforts to bring rapid whole-genome sequencing to these cases, first at Children's Mercy Hospital in Kansas City and more recently at RCIGM, using artificial intelligence and other approaches to speed up sequencing and analyses.

But while the RCGIM team has brought sequencing-based diagnostic times down to around 13.5 hours, on average, optimal management and treatment of these conditions has continued to lag even after genetic culprits are uncovered in the genome, he noted, in part because clinicians may lack familiarity with genomic medicine.

"These disorders are managed by regional super-specialists, but the testing and the diagnoses are being reported to front-line neonatologists and intensivists," Kingsmore said. "So we needed to upskill the latter group with information that the former group would normally provide for a variable period of time, depending on whether that health system actually has a super-specialist available who can take over management of the patient."

Bridging this gap may help with consulting and communicating results to affected families, as well as getting confirmatory testing, initial management, and treatment underway, he explained. To do that, the team first considered the factors that might stand in the way — from genomic literacy to the availability of established treatment guidance and effectiveness data.

From there, the researchers went through a series of data compilation, data analysis, and artificial intelligence steps to come up with a resource that offers diagnostic reports on conditions caused by alterations affecting 97 genes that have effective treatment or management options — from medications or medical devices to surgical or dietary interventions.

"We wanted to provide something that would be linked to individual diagnostic reports and just contain what a front-line M.D. would need to know to care for a specific patient with a specific genetic disease diagnosis," Kingsmore said.

Using a rare cardiac dysrhythmia condition called Timothy syndrome as an example, Kingsmore walked conference attendees through the GTRx information page for this condition. In that case, the GTRx page provides information on Timothy syndrome, proposed interventions and their efficacy, and more, including a warning that highlights the hypoglycemia risk associated with the use of general anesthesia in children with the condition.

In its current form, the GTRx resource includes data from 10 large genetic resources such as OMIM, PubMed, and DrugBank, and has been integrated into the RCIGM sequencing pipeline, part of its clinical genomics program.

Kingsmore noted that "treatments are evolving fairly rapidly" for some of the conditions included in the collection, "so there will be a need for community-based, ongoing curation" as the resource continues to develop and grow.

In an abstract accompanying the presentation, he and his co-authors argued that the GTRx "will facilitate broad implementation of optimal acute treatment for children with rapidly progressive genetic diseases by front-line ICU physicians."