Global genomic collaboration improves lives and treatment for children with epilepsy

Please note this article includes a story that covers the topic of baby loss.

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.

Published in The Lancet Neurology today, this international study sequenced the genomes of 100 babies under the age of one with unexplained seizures from four countries (England, USA, Canada and Australia) to better understand the potential strengths of early, broad genome sequencing (a process which looks for changes across the entire genome) for infantile epilepsy.

The researchers used rapid genome sequencing (rGS) to investigate the impact of an expedited genetic diagnosis on care for the first time. Across all children enrolled in the study, 43 per cent received a diagnosis within weeks, and that diagnosis impacted prognosis in nearly 90 per cent of those cases, guiding treatment options for over half.

Called Gene-STEPS, Shortening Time of Evaluation in Paediatric epilepsy Services, the study is the first collaboration launched through the International Precision Child Health Partnership (IPCHiP), an international consortium (Boston Children’s Hospital, Murdoch Children’s Research Institute with The Royal Children’s Hospital, The Hospital for Sick Children (SickKids) and UCL Great Ormond Street Institute of Child Health (UCL GOS ICH) and Great Ormond Street Hospital) that leverages each institution’s expertise and genomic infrastructure to accelerate discovery and the development of therapies for children.

The UK team, led by Dr Amy McTague (GOSH and UCL GOS ICH) utilised expertise within the Translational Research Team at the North Thames Genomics Laboratory Hub (NT GLH) to establish a new rGS pathway for children enrolled in the study at GOSH.

Currently, there are 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.

The UK arm of the study was part-funded by Great Ormond Street Hospital Children’s Charity (GOSH Charity) and the National Institute for Health and Care Research (NIHR) GOSH Biomedical Research Centre with support from Young Epilepsy. The collaboration utilised expertise and infrastructure from the Translational Research team at the 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.

This powerful in-house sequencing technique 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, fully-informed decision making and often further clinical investigations.

In this study, both biological parents and the child underwent rGS, known as ‘trio’ sequencing, to more quickly understand whether gene changes in the children were inherited or new to the child (de novo). These insights are important for families to understand how the results impact their lives and their plans for any future children.

Please note this story covers the topic of baby loss

Leo Bush was born prematurely on the 24 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 what was wrong with Leo. 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.

Andy and Sofie have recently welcomed a baby daughter into the world and are enjoying their time together as a family.

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.

This study was funded by the American Academy of Pediatrics, Boston Children’s Hospital Children’s Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Children’s Charity, Medical Research Council, Murdoch Children’s Research Institute, National Institute of Child Health and Human Development, NIHR Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, and University of Toronto McLaughlin Centre.