O2077: Prospective Cohort Pilot Study of Rapid Genome Sequencing in Neonatal and Infantile Epilepsy

Background: Neonatal and infantile-onset epilepsies are collectively common (1:1000 live births) and carry significant disease burden. The majority have presumed genetic etiologies, and early identification of genetic diagnoses has the potential to inform clinical management and improve outcomes. A major challenge is that genetic testing often takes months to years, while infants have progressive neurologic sequelae from uncontrolled seizures and/or underlying disease. We aimed to delineate the genetic landscape of neonatal and infantile-onset epilepsies and determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing (rGS) in this population.

Methods: As the United States site of the Gene-STEPS (Shortening Time to Evaluation in Pediatric epilepsy Services) study, an international, multi-center, prospective cohort study of the International Precision Child Health Partnership, we enrolled infants presenting to Boston Children’s Hospital (BCH) with new-onset epilepsy over one year. We included and phenotyped infants with seizure onset at < 12 months recruited within 6 weeks of site presentation. We excluded infants with simple febrile seizures, provoked seizures, or known genetic cause. Families were consented to the study and clinical rGS, blood samples were collected from the infant and available biological parents, rGS and analysis were performed at a clinically accredited laboratory, and results were returned to families and treating clinicians. We assessed the short-term clinical utility of rGS. This study was approved by the BCH Institutional Review Board.

Results: During a one-year pilot, parents of 91% of eligible infants consented. We enrolled 34 infants with new-onset epilepsy, 41% female, with median age of seizure onset 115 days (interquartile range (IQR) 36-178) and 10/34 (29%) with neonatal-onset. Twenty-eight infants were recruited from inpatient units (10 intensive care and 18 non-intensive care) and six from outpatient. For 15/34 (44%) infants, we identified a genetic diagnosis, with median time from enrollment to rGS result 15 days (IQR 12-17). rGS revealed genetic heterogeneity, with 14 genes and genomic regions implicated across the 15 patients. For 6/15 (40%), diagnoses were not made by standard first-tier clinical genetic testing. Genetic diagnoses had immediate clinical utility in all cases, informing treatment in 40% (6/15), additional evaluation in 47% (7/15), prognosis in 93% (14/15), and goals of care in 7% (1/15). All families received recurrence risk counseling.

Conclusion: Gene-STEPS is the first prospective study of rapid sequencing in a disease-specific cohort and the first comprised of patients mostly outside intensive care settings. Our findings support implementation of rGS in the clinical care of infants with new-onset epilepsy, providing a paradigm for additional disease cohorts. Further, genetic diagnoses deepen our understanding of the heterogeneous genetic mechanisms underlying neonatal and infantile-onset epilepsies. Future research will be needed to understand the personal and long-term utility of early genetic diagnosis in this population.