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Title: | Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study. | Austin Authors: | D'Gama, Alissa M;Mulhern, Sarah;Sheidley, Beth R;Boodhoo, Fadil;Buts, Sarah;Chandler, Natalie J;Cobb, Joanna;Curtis, Meredith;Higginbotham, Edward J;Holland, Jonathon;Khan, Tayyaba;Koh, Julia;Liang, Nicole S Y;McRae, Lyndsey;Nesbitt, Sarah E;Oby, Brandon T;Paternoster, Ben;Patton, Alistair;Rose, Graham;Scotchman, Elizabeth;Valentine, Rozalia;Wiltrout, Kimberly N;Hayeems, Robin Z;Jain, Puneet;Lunke, Sebastian;Marshall, Christian R;Rockowitz, Shira;Sebire, Neil J;Stark, Zornitza;White, Susan M;Chitty, Lyn S;Cross, J Helen;Scheffer, Ingrid E ;Chau, Vann;Costain, Gregory;Poduri, Annapurna;Howell, Katherine B;McTague, Amy | Affiliation: | Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia. Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA. Department of Neurology, Great Ormond Street Hospital, London, UK. Department of Paediatric Neurology, Aachen University Hospital, Germany. North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK. Murdoch Children's Research Institute, Melbourne, VIC, Australia. Division of Genome Diagnostics, Hospital for Sick Children, Toronto, ON, Canada. Department of Neurology, Great Ormond Street Hospital, London, UK. Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada. Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA. Department of Genetic Counselling, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Division of Neurology, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada. North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK; Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK. Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA. North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK. Department of Paediatrics, Frimley Park Hospital, Frimley Health NHS Foundation Trust, Frimley, UK. North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK. Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA. Program in Child Health Evaluative Sciences, SickKids Research Institute, Toronto, ON, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada. Division of Neurology, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Pathology, University of Melbourne, Melbourne, VIC, Australia. Division of Genome Diagnostics, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Research Computing, Boston Children's Hospital, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. DRIVE Centre, Great Ormond Street Hospital for Children, London, UK. Victorian Clinical Genetics Service, Melbourne, VIC, Australia. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK; Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK. Department of Neurology, Great Ormond Street Hospital, London, UK; Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK. Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Austin Health, and Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Department of Neurology, Royal Children's Hospital, Melbourne, VIC, Australia. Division of Neurology, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada. Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA. Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Neurology, Royal Children's Hospital, Melbourne, VIC, Australia. Department of Neurology, Great Ormond Street Hospital, London, UK; Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK. The Florey Institute of Neuroscience and Mental Health |
Issue Date: | Sep-2023 | Publication information: | The Lancet. Neurology 2023-09; 22(9) | Abstract: | Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. 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 Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/33563 | DOI: | 10.1016/S1474-4422(23)00246-6 | ORCID: | Journal: | The Lancet. Neurology | Start page: | 812 | End page: | 825 | PubMed URL: | 37596007 | ISSN: | 1474-4465 | Type: | Journal Article | Subjects: | Epilepsy/diagnosis Epilepsy/genetics |
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