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(Abst. 3.401), 2018

Exome Sequencing of a Pediatric Refractory Status Epilepticus Cohort (the pSERG Cohort)
Authors: Erin L. Heinzen, Institute of Genomic Medicine, Columbia University; Justice Clark, Boston Children’s Hospital, Harvard Medical School; Aggarwal Vimla, Institute of Genomic Medicine, Columbia University; Marta Amengual Gual, Boston Children’s Hospital, Harvard Medical School; Ravindra Arya, Cincinnati Children's Hospital Medical Center, University of Cincinnati; Jessica L. Carpenter, Children’s National Medical Center, George Washington University School of Medicine and Health Sciences; Kevin E. Chapman, Children’s Hospital Colorado, University of Colorado School of Medicine; William D. Gaillard, Children’s National Medical Center; Marina Gaínza-Lein, Boston Children’s Hospital, Harvard Medical School; Tracy A. Glauser, Cincinnati Children's Hospital Medical Center, University of Cincinnati; Joshua L. Goldstein, Northwestern University Feinberg School of Medicine, Chicago, IL; Michele Jackson, Boston Children’s Hospital, Harvard Medical School; Kush Kapur, Boston Children's Hospital, Harvard Medical School. Boston, MA, United States.; Tiffani L. McDonough, Columbia University Medical Center; Mohamad A. Mikati, Duke University; Katrina Peariso, Cincinnati Children's Hospital Medical Center, University of Cincinnati; Iván Sánchez Fernández, Boston Children’s Hospital, Harvard Medical School; Hospital Sant Joan de Déu, Universidad de Barcelona; Kate E. Stanley, Institute of Genomic Medicine, Columbia University; Robert C. Tasker, Boston Children’s Hospital, Harvard Medical School; Dmitry Tchapyjnikov, Duke University Medical Center; Alejandra Vasquez, Boston Children’s Hospital, Harvard Medical School; Mark S. Wainwright, Seattle Children's Hospital; Angus Wilfong, University of Arizona College of Medicine; Korwyn Williams, University of Arizona College of Medicine; David Goldstein, Institute of Genomic Medicine, Columbia University; and Tobias Loddenkemper, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Content: Rationale: Status epilepticus is a condition characterized by a continuous seizure or intermittent seizures without regaining consciousness for more than five minutes. If the persistent seizure activity fails to respond to medications, there is a high risk of neuronal injury, permanent changes to the neuronal circuitry, and in some cases death. It is unclear if status epilepticus is an extension of the epileptogenic processes that gives rise to the seizure in the first place, or if there is a distinct biological mechanism. We sought to use exome sequencing of a cohort of pediatric individuals who have had at least one instance of refractory status epilepticus (rSE) to study the underlying genetic basis of the condition. Methods: Eighty-one pediatric patients with prolonged convulsive seizures were enrolled and DNA collected at eight sites as part of the Pediatric Status Epilepticus Research Group (pSERG). Common inclusion criteria for our ongoing multicenter, prospective observational cohort study with prolonged convulsive seizures and rSE consist of: 1) age 1 month to 21 years; 2) convulsive seizures at onset; and 3) application of 2 or more anti-seizure medications for convulsive seizures, and 4) consent obtained and assent obtained, when applicable.  We excluded patients with: 1) non-convulsive SE detected on EEG (without convulsive seizures at onset); and 2) non-convulsive status epilepticus and infrequent myoclonic jerks, and 3) unable to obtain consent/assent. Exome sequencing was performed on leukocyte DNA from 81 probands, including 22 full trios. We performed two analyses using established analysis pipelines in the Institute for Genomic Medicine at the Columbia University Irving Medical Center: (1) a gene-level collapsing analysis comparing the 81 cases to ~4000 population controls to look for a shared genetic basis across the cohort, and (2) a research diagnostic analysis of each individual’s sequence data to look for causative variants based on ACMG-AMP criteria. Results: Individual level analyses revealed pathogenic or likely pathogenic variants (based on ACMG-AMP criteria) in 22% of the cases in the genes SCN8A(n=3), MECP2(n=3), SCN1A(n=2), PCDH19(n=2), SCN2A(n=1),ATP1A3(n=1), In the case-control comparison, we found no single gene with significantly more cases harboring a rare, putatively functional variant when compared to population controls, after correcting for all the genes in the genome.  Conclusions: Pediatric patients presenting with rSE have an overall high frequency of genetic epileptic encephalopathy diagnoses, including some of the most severe genetic epilepsy diagnoses. Funding: Institute for Genomic Medicine (Columbia University), Epilepsy Research Fund, and Pediatric Epilepsy Research Foundation