Multicenter Study

. 2023 Sep;22(9):812-825.

doi: 10.1016/S1474-4422(23)00246-6.

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

Alissa M D'Gama¹, Sarah Mulhern², Beth R Sheidley³, Fadil Boodhoo⁴, Sarah Buts⁵, Natalie J Chandler⁶, Joanna Cobb⁷, Meredith Curtis⁸, Edward J Higginbotham⁸, Jonathon Holland⁴, Tayyaba Khan⁹, Julia Koh³, Nicole S Y Liang¹⁰, Lyndsey McRae¹¹, Sarah E Nesbitt¹², Brandon T Oby³, Ben Paternoster⁶, Alistair Patton¹³, Graham Rose⁶, Elizabeth Scotchman⁶, Rozalia Valentine³, Kimberly N Wiltrout¹⁴; Gene-STEPS Study Group; IPCHiP Executive Committee; Robin Z Hayeems¹⁵, Puneet Jain¹⁶, Sebastian Lunke¹⁷, Christian R Marshall¹⁸, Shira Rockowitz¹⁹, Neil J Sebire²⁰, Zornitza Stark²¹, Susan M White²¹, Lyn S Chitty¹², J Helen Cross²², Ingrid E Scheffer²³, Vann Chau¹⁶, Gregory Costain²⁴, Annapurna Poduri¹⁴, Katherine B Howell²⁵, Amy McTague²⁶

Affiliations

¹ 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.
² Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
³ Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁴ Department of Neurology, Great Ormond Street Hospital, London, UK.
⁵ Department of Paediatric Neurology, Aachen University Hospital, Germany.
⁶ North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK.
⁷ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁸ Division of Genome Diagnostics, Hospital for Sick Children, Toronto, ON, Canada.
⁹ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
¹⁰ Department of Genetic Counselling, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹¹ Division of Neurology, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada.
¹² 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.
¹³ Department of Paediatrics, Frimley Park Hospital, Frimley Health NHS Foundation Trust, Frimley, UK.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
¹⁸ Division of Genome Diagnostics, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁹ 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.
²⁰ DRIVE Centre, Great Ormond Street Hospital for Children, London, UK.
²¹ Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
²² Department of Neurology, Great Ormond Street Hospital, London, UK; Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
²³ 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.
²⁴ 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.
²⁵ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Neurology, Royal Children's Hospital, Melbourne, VIC, Australia.
²⁶ 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. Electronic address: a.mctague@ucl.ac.uk.

PMID: 37596007
PMCID: PMC11860300
DOI: 10.1016/S1474-4422(23)00246-6

Multicenter Study

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

Alissa M D'Gama et al. Lancet Neurol. 2023 Sep.

. 2023 Sep;22(9):812-825.

doi: 10.1016/S1474-4422(23)00246-6.

Authors

Affiliations

¹ 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.
² Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
³ Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁴ Department of Neurology, Great Ormond Street Hospital, London, UK.
⁵ Department of Paediatric Neurology, Aachen University Hospital, Germany.
⁶ North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK.
⁷ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁸ Division of Genome Diagnostics, Hospital for Sick Children, Toronto, ON, Canada.
⁹ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
¹⁰ Department of Genetic Counselling, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹¹ Division of Neurology, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada.
¹² 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.
¹³ Department of Paediatrics, Frimley Park Hospital, Frimley Health NHS Foundation Trust, Frimley, UK.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
¹⁸ Division of Genome Diagnostics, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁹ 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.
²⁰ DRIVE Centre, Great Ormond Street Hospital for Children, London, UK.
²¹ Victorian Clinical Genetics Service, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
²² Department of Neurology, Great Ormond Street Hospital, London, UK; Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
²³ 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.
²⁴ 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.
²⁵ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Neurology, Royal Children's Hospital, Melbourne, VIC, Australia.
²⁶ 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. Electronic address: a.mctague@ucl.ac.uk.

PMID: 37596007
PMCID: PMC11860300
DOI: 10.1016/S1474-4422(23)00246-6

Erratum in

Correction to Lancet Neurol 2023; 22: 812-25.
[No authors listed] [No authors listed] Lancet Neurol. 2023 Dec;22(12):e13. doi: 10.1016/S1474-4422(23)00411-8. Epub 2023 Oct 17. Lancet Neurol. 2023. PMID: 37863089 No abstract available.

Abstract

Background: 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.

Methods: 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.

Findings: 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).

Interpretation: 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.

Funding: 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.

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Conflict of interest statement

Declaration of interests APa is a current member of the National Institute of Health and Clinical excellence (NICE) technology appraisal committee B and has a financial interest in Genedrive PLC. KW has consulted for Stoke Therapeutics. JHC has received renumeration for lectures by GW pharma/Jazz, UCB/Zogenix, Biocodex, and Biogen; is a member of the Data Monitoring and Safety Committee for Admiral Trial (Stroke Therapeutics); and is Chair of the Medical Advisory Board for Matthews Friends, Dravet UK, and Hope for Hypothalamic Hamartoma. IES has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, and Eisai; has served as an investigator for Anavex Life Sciences, Cerecin, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder, Epygenyx, ES-Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, and Biohaven Pharmaceuticals; and is a Non-Executive Director of Bellberry and a Director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies. IES might accrue future revenue on pending patent WO61/010176 (filed in 2008; therapeutic compound); has a patent for SCN1A testing held by Bionomics and licensed to various diagnostic companies; has a patent molecular diagnostic or theranostic target for benign familial infantile epilepsy (PRRT2; 2011904493, 2012900190, and PCT/AU2012/001321 [TECH ID:2012-009]). GC has received honorarium from CADTH and serves as the Co-Lead of the Can-GARD Initiative and on the SickKids Precision Child Health steering committee. APo serves on the scientific advisory boards for TevardBio and Syngap Research Fund, and on the American Epilepsy Society Board of Directors. KBH has received support from RogCon Biosciences and Praxis Precision Medicines. AM has received consulting fees from Rocket Pharmaceuticals; honorarium from Jazz Pharmaceuticals; support for attending conferences from Jazz Pharmaceuticals and European Paediatric Neurology Society; fees for participating on boards for Biogen and Biocodex; and serves unpaid roles on the ILAE Genetic Literacy Task Force, EPICARE, and Great Ormond Street Hospital National Institute for Health and Care Research Biomedical Research Centre Chair of Junior Faculty. All other authors declare no competing interests.

Figures

**Figure 1**
Study profile GS=genome sequencing. *Not via this study.

**Figure 2**
Rapid GS workflow and summary of genetic diagnoses (A) Rapid GS workflow and time intervals, created with BioRender.com. (B) Genetic diagnoses arranged by age at seizure onset. Each square represents an infant who received a genetic diagnosis. The affected gene or genomic region is denoted in the square. The infant with a diagnostic *SCN2A* variant and seizure onset in the second month of life classified as self-limited neonatal epilepsy was born prematurely and was younger than 44 weeks postmenstrual age at seizure onset. (C) Types of variants in diagnostic cases. Data are n (%) of 46 total variants. (D) Mode of inheritance of variants in diagnostic cases. Data are n (%) of 43 total diagnoses. GS=genome sequencing. DEE=developmental and epileptic encephalopathy.

See this image and copyright information in PMC

Comment in

Genome sequencing for the fast diagnosis of early-onset epilepsies.
Johannesen KM, Møller RS. Johannesen KM, et al. Lancet Neurol. 2023 Sep;22(9):773-774. doi: 10.1016/S1474-4422(23)00289-2. Lancet Neurol. 2023. PMID: 37596000 No abstract available.
Rapid genome sequencing for infantile-onset epilepsy within a national health-care setting.
Robinson HK, Stals K, Hill S, Parrish A, Baple EL. Robinson HK, et al. Lancet Neurol. 2024 Feb;23(2):139-140. doi: 10.1016/S1474-4422(23)00429-5. Lancet Neurol. 2024. PMID: 38267181 No abstract available.
Rapid Whole Genome Sequencing: It Is Feasible! When Can We Implement It?
Joshi C. Joshi C. Epilepsy Curr. 2024 Mar 25;24(3):171-173. doi: 10.1177/15357597241237349. eCollection 2024 May-Jun. Epilepsy Curr. 2024. PMID: 38898915 Free PMC article. No abstract available.

References

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1. McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15:304–316. - PubMed
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Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

Affiliations

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

Comment in

References

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Medical