Researchers at UCL and Great Ormond Street Hospital have collaborated with institutes across the world to use rapid genome sequencing to provide a diagnosis for children with unexplained epilepsy and significantly benefit their care.
Epilepsy in children ranges in severity and can leave families and carers with many questions about their child’s future health. While genetic testing to find the cause of epilepsy is possible it can take a long time - leaving families waiting for answers.
The international study, published in The Lancet Neurology, sequenced the genomes of 100 babies under the age of one with unexplained seizure from four countries (England, USA, Canada and Australia) leveraging expertise and genomic infrastructure from each.
The research used rapid genome sequencing (rGS), which looks for changes across the entire genome, to investigate the impact of immediate genetic diagnosis on care for the first time.
Across all children enrolled in the study, 43 per cent received a diagnosis, within weeks. This diagnosis then went on to impact prognosis in nearly 90 per cent of those cases and it guided treatment options in over half of patients.
The Gene-STEPS, Shortening Time of Evaluation in Paediatric epilepsy Services study is the first collaboration launched through the International Precision Child Health Partnership (IPCHiP), an international consortium between UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Boston Children’s Hospital, Murdoch Children’s Research Institute with the Royal Children’s Hospital and The Hospital for Sick Children (SickKids).
Dr Amy McTague (UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital), who led the UK team, said: "It’s incredibly exciting to share the results from the first phase of this IPCHiP project and, importantly, it is fantastic that this research has provided powerful evidence for the clinical benefits of rapid genomic sequencing in young children with new-onset epilepsy.
"Through a global collaboration of expert researchers, we have shown how this testing can be used, across four different healthcare systems, to rapidly diagnose children with epilepsy, finding an answer in over 40% and guiding treatment in over 50% of these children.
"This has the potential to impact many families across the world and provide much needed information to clinical teams in charge of their care. We are incredibly grateful to every family that took part in this study, research like this is only possible because of them."
There are currently more than 800 known different genetic causes of infantile epilepsy, and many have similar symptoms during early childhood. Unlike more targeted genetic testing that is often used to confirm a suspected diagnosis, genome sequencing looks for any changes in a person’s DNA that may explain a medical condition, analysing the entire genome.
This allowed researchers to not only provide a rapid diagnosis for many families, but also had an immediate impact on clinical care - allowing for faster access to correct treatments, full-informed decision making and often further clinical investigations.
In this study, rGS was used to deliver ’trio’ sequencing, testing both parents and the child, to more quickly understand whether gene changes in the children were inherited or new to the child (de novo). These insights allow families to understand how the results impact their lives and their plans for any future children.
The international research team is continuing to follow-up with clinicians and study participants to understand how rGS has influenced children’s development long-term. The GOSH team are also hoping that they will be able to bring this test into clinical service, giving families across the country access.
Investigator on the project, Professor Helen Cross (Director of the UCL Great Ormond Street Institute of Child Health and Honorary consultant in paediatric neurology at GOSH), said: "The results published today highlight how this worldwide collaboration is already enabling us to combine collective knowledge and research expertise to benefit children around the world. Through support in the UK from the NIHR GOSH Biomedical Research Centre and GOSH Charity, we have been able to demonstrate the power that rapid genetic sequencing can have for children with epilepsy.
"Embedding research into all aspects of care at GOSH, through the partnership with the UCL Great Ormond Street Institute of Child Health, enables studies such as this one to bring cutting-edge technology and developments into clinical practise."
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The collaboration utilised expertise and infrastructure from the Translational Research team at the North Thames Genomics Laboratory Hub (NT GLH), as well as data teams from within the GOSH Digital Research Environment to rapidly develop a rGS pathway within an established clinical genomics facility.
Professor Thomas Voit (Director of the NIHR GOSH BRC and Professor at UCL Great Ormond Street Institute of Child Health), said: "This paper highlights the impact that funding translational research and international collaborations can have on families and our clinical practice. At the NIHR GOSH BRC we are proud to continue to support research through the North Thames Genomics Laboratory Hub to understand how integrating rapid genetic testing into routine care can benefit families around England."
Leo Bush was born prematurely on the 24th of October 2021, and, despite early positive signs, he rapidly began to develop serious symptoms including seizures. Despite lots of invasive testing and attempted treatments doctors struggled to understand the problem. At six weeks old he was transferred to GOSH for specialist treatment and almost immediately enrolled in the IPCHiP study.
Approximately two weeks after giving samples of their blood for testing, the family were told that Leo had a very rare genetic diagnosis of BRAT1-related neurodevelopmental disorder caused by inheriting a faulty copy of the gene from both his parents. The mutation causes a very severe form of intractable epilepsy in children. There is currently no treatment for the condition and management of symptoms is incredibly difficult. Babies with this genetic epilepsy rarely survive beyond first six months of life.
Leo was 79 days old when he passed away in Andy and Sofie’s arms on January 10 2022.
Leo’s dad, Andy, said: "It was completely and utterly heart-breaking but getting a diagnosis provided us with a reason. It allowed us to start processing. The diagnosis made an impossible situation easier. We may not ever find a cure for BRAT1 but having a diagnosis - an answer - was, for us, so powerful."
Sofie, Leo’s mum, said: "We really want to build the understanding people have of how powerful a genetic diagnosis can be. We also know how lucky we were to be at GOSH and be part of this research project - we desperately want to see tests like this rolled out more widely so that everyone has the access we did. The test was so simple - just a blood test. After so many invasive procedures that provided no answers, it was so powerful to us that the information we needed came from a simple blood test for Leo."
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