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Rapid Sequencing Yields High Newborn Epilepsy Diagnostic Rates in Gene-STEPS Study


NEW YORK – Early results from a multinational genomic study of infantile epilepsy found that rapid whole-genome sequencing (WGS) improved diagnostic yield over more common methods, giving hope to those wishing whole-genome testing would become a standard of care for diagnosing and developing treatment plans for genetic disorders in newborns.

A study published this month in Lancet Neurology described Gene-Shortening Time of Evaluation in Paediatric epilepsy Services (Gene-STEPS), the pilot and initial flagship project of the International Precision Child Health Partnership (IPCHiP). The paper reported data on the first 100 families participating in Gene-STEPS, representing enrollment for the 12 months ended Aug. 31, 2022.

Using rapid WGS of parent-child trios, clinicians were able to diagnose infantile epilepsy in 43 of the 100 babies studied, close to the 48 percent yield found in an earlier study with nonrapid genome sequencing and far higher than what other researchers achieved with microarrays, gene panels, and exome sequencing.

"[W]e demonstrate immediate clinical utility of genetic diagnoses for infants and their families in most cases," the authors wrote. "Our findings provide support to prompt the use of state-of-the-art rapid genomic testing to facilitate early etiological diagnosis that can inform urgent targeted management in this vulnerable population."

IPCHiP, and by extension, Gene-STEPS, includes Murdoch Children's Research Institute in Melbourne, Australia, the Toronto-based Hospital for Sick Children (SickKids) in Canada, University College London's Great Ormond Street Institute of Child Health in the UK, and Boston Children's Hospital in the US.

The IPCHiP coalition formed in 2019. "Since then, we've been looking to leverage the expertise and resources that we have across these four leading children's hospitals to try to advance different aspects of pediatric precision care," explained Gregory Costain, a neuropsychiatric genetics specialist at SickKids and a coauthor of the Lancet Neurology paper.

Costain said that the goal is to make rapid WGS a "first-tier test" for infants with unexplained epilepsy. The paper suggested that Gene-STEPS could be exported to other diseases where the cause is unclear but thought to be genetic.

All four sites conducted sequencing on short-read Illumina instruments, but each institution could choose different methods and tools for secondary and tertiary analysis.

With an eye to eventually supporting rapid WGS for newborns across the province of Ontario, SickKids has set up new protocols and workflows in its clinical diagnostics lab. Costain said that SickKids uses Illumina's Dragen software for secondary analysis, including variant calling and alignment. For tertiary analysis, the hospital has turned to AI-based variant curation and interpretation application Emedgene, another Illumina-owned product.

Boston Children's outsources its rapid WGS to Stamford, Connecticut-based company GeneDx. The hospitals in Australia and the UK are using national and subnational genomics infrastructure for this study.

"In all cases, we were moving the paradigm forward by using research funding to support the sequencing, because in none of these four places would rapid genome sequencing be considered a routine clinical test for all of these babies with epilepsy," Costain explained.

A lot still needs to happen for rapid WGS to become a routine part of newborn screening and pediatric care, such has integration into clinical workflows as well as education for frontline practitioners.

"As a medical geneticist, I'm very invested in this idea of being able to access timely, comprehensive genetic testing for patients," Costain said, but that will require the generation of an evidence base that goes beyond diagnostic yield.

"I think we can mostly agree that genome sequencing is going to find more diagnoses than a targeted approach," he said. "The question is whether it's cost-effective and whether there are other downstream consequences for the better or for the worse that we need to be made aware of before it gets integrated as a healthcare task."

Gene-STEPS is one of several programs around the world trying to replace tandem mass spectrometry with genome sequencing for newborn screening, though it may be the first to look at epilepsy specifically. There is some institutional crossover; Boston Children's, for example, participates in BabySeq, while Murdoch Children's Research Institute is participating in a new project called Baby Beyond.

GeneDx, formerly known as Sema4, is involved in the Genomic Uniform-screening Against Rare Diseases in All Newborns (GUARDIAN) study, led by Wendy Chung, who left Columbia University Irving Medical Center in New York this year to become chief of pediatrics at Boston Children's.

GeneDx Chief Medical Officer Paul Kruska said that there is room for all of these efforts. "A diagnostic study with sick patients, such as [Gene-STEPS] and a screening study with healthy patients, such as GUARDIAN, complement each other well," Kruska said via email. "They both aim to decrease the diagnostic odyssey by sequencing earlier and allowing for precision diagnosis and treatment."

While the Lancet Neurology paper didn't touch on the idea of the diagnostic odyssey, Costain said that these initial Gene-STEPS results did show potential for reducing the amount of time families have to wait for a diagnosis — or for ruling out certain conditions.

"We're starting to appreciate the value of negative genetic testing in some families," he said. Rather than creating disappointment when sequencing does not turn up evidence of a Mendelian cause, a negative or normal result could lead to smarter treatment decisions for infantile seizures, he explained.

"For some families, there's value in getting a negative genome sequencing result right away," Costain added. "There might be some value in a negative result being reassuring with respect to seizure outcome and decreasing the likelihood of there being a severe epileptic encephalopathy or genetic epilepsy in some of these kids."

Gene-STEPS operates on a federated model, so each site is responsible for obtaining its own funding. Costain said that the study is adequately funded at all four locations for several years.

In terms of technology development, Costain believes there is an opportunity for Gene-STEPS to expand variant calling.

Costain said that genome-wide, short-tandem repeat expansions, and mitochondrial DNA variation "were not consistently being called" at all four participating sites. "Those types of variation are not known to be major contributors to the etiologies of infantile epilepsy, but there is the potential to still diagnose some conditions in that way and to make new discoveries," he said.

Costain said that the researchers plan on continuing their work for several years. If funding allows, they would like to follow the children long term to create a longitudinal study of disease trajectories based on genetics and interventions.

"There's certainly been a lot of work in studying the role for rapid genome sequencing in pediatric medicine, especially in critically ill babies," Costain said. "One of the things that we hadn't seen anyone do yet is follow those children out for a period of years to try to get a better sense of how did that early intervention with genome sequencing shape what's to come?"

There are several categories of work that the Gene-STEPS team wants to explore going forward, the most achievable being the continuation of research on the same children to understand how the preliminary results might inform future care, according to Costain.

The researchers will also continue to analyze data in "novel ways," such as by calling new variant types and variant clusters in search of previously unknown risk factors for epilepsy.

In addition, Costain said he believes the research infrastructure assembled for Gene-STEPS "could potentially be expanded to a number of other more common presentations in children where we know that there's a significant genetic component," such as hypotonia.

"I expect that we'll be able to use the framework of this study and recapitulate it in other populations with the idea of not restricting ourselves necessarily to children who are in an intensive care setting," he said.

There are plans to expand Gene-STEPS to other institutions, though those vary from jurisdiction to jurisdiction and are of course dependent on funding. Genomics England is supporting Gene-STEPS indirectly through Great Ormond Street. Australia also has a "strong national system" for rapid genomic testing, Costain noted.

SickKids is one of the leaders of a provincial program called Genome-wide Sequencing Ontario that offers genome sequencing for rare diseases through a hub-and-spoke model. Sites across Ontario collect samples and provide counseling based on test results, but all the sequencing is performed at SickKids, which also splits all tertiary analysis and interpretation responsibilities with Children's Hospital of Eastern Ontario in Ottawa.

Costain believes that Gene-STEPS could eventually become part of that program, which is run by the provincial health ministry, but that idea is purely aspirational right now.

"It is going to require ongoing continuing education of different types of providers and some efforts to improve the genomic literacy in the public to make sure that they are understanding what the tests will and won't do," Costain said.