Rapid Genome Sequencing in Infantile Epilepsy: Shifting the Diagnostic Paradigm
Abstract number :
2.354
Submission category :
12. Genetics / 12A. Human Studies
Year :
2023
Submission ID :
295
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Alissa D'Gama, MD PhD – Boston Children's Hospital
Sarah Mulhern, MGenCouns – Murdoch Children’s Research Institute; Beth Sheidley, MS – Boston Children's Hospital; J. Helen Cross, MB ChB PhD – UCL Great Ormond Street Institute of Child Health; Ingrid Scheffer, MBBS PhD – University of Melbourne; Vann Chau, MD – Hospital for Sick Children; Gregory Costain, MD PhD – Hospital for Sick Children; Annapurna Poduri, MD MPH – Boston Children's Hospital; Katherine Howell, MBBS PhD – Royal Children’s Hospital; Amy McTague, MBChB PhD – UCL Great Ormond Street Institute of Child Health; Gene-STEPS Study Team, N/A – Multiple Institutions
Rationale: Neonatal and infantile-onset epilepsies are common and carry significant disease burden. The majority have presumed genetic etiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We aimed to delineate the genetic landscape of infantile epilepsies and determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing (rGS) in this population.
Methods: For this prospective cohort study, we enrolled participants and available biological parents from inpatient and outpatient settings at four pediatric referral centers in Australia, Canada, the United Kingdom, and the United States over one year. This study was approved by the Institutional Review Board at each center. We included and phenotyped infants with seizure onset at < 12 months; we excluded infants with simple febrile or provoked seizures or known acquired or genetic cause. rGS and analysis were performed at clinically accredited laboratories and results returned to families. We assessed the clinical utility of rGS.
Results: Parents of 91% of eligible infants consented to study participation. We enrolled 100 infants with new-onset epilepsy, 41% female, with median age of seizure onset 128 days (IQR 46-192). For 43/100 (43%), we identified genetic diagnoses, with median turnaround time from enrollment to rGS result 21 days (IQR 15-23) and median time from seizure onset to rGS result 37 days (IQR 25-59) (Figure 1). Genetic diagnosis was associated with neonatal vs. infantile seizure onset (14/19 [75%] vs. 29/81 [36%], p=0·0027), referral setting (12/17 [71%] intensive care, 19/43 [44%] non-intensive care inpatient, 12/40 [28%] outpatient, p=0·0178), and epilepsy syndrome (13/15 [87%] self-limited epilepsies, 18/51 [35%] developmental and epileptic encephalopathies, 12/34 [35%] other syndromes, p=0·0010). rGS revealed genetic heterogeneity, with 34 unique genes/genomic regions implicated (Figure 2). Genetic diagnoses had immediate clinical utility, informing treatment (56% [24/43]), additional evaluation (65% [28/43]), prognosis (86% [37/43]), and recurrence risk counselling (all cases).
Conclusions: This study of rapid genome sequencing in infantile epilepsies is the first study of rapid sequencing in a disease-specific cohort and the first comprised of patients primarily outside of intensive care settings. Our findings support implementation of rGS in the clinical care of infants with new-onset epilepsy, providing a paradigm for other unexplained diseases. Genetic diagnoses provide clinical utility and deepen our understanding of the heterogeneous genetic mechanisms underlying infantile epilepsies.
Funding: AAP, Australia MRFF, AERF, BCH CRDC Initiative, CIHR, Epilepsy Canada, Feiga Bresver Academic Foundation, GOSH Charity, MRC, Melbourne Children's, MCRI, NHMRC, NICHD, NIHR GOSH BRC, One8 Foundation, OBI, Robinson Family Initiative for Transformational Research, Rosetrees Trust, The RCH Foundation, University of Toronto McLaughlin Centre, Wellcome Trust.
Genetics