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(Abst. 2.348), 2015

Whole Exome and Methylation Profiling identifies Candidate Aberrations in Epilepsy Surgery Patients Who Died of SUDEP
Authors: Daniel Friedman, Arline Faustin, Kasthuri Kannan, Seema Shroff, Cheddhi Thomas, Matthias Karajannis, Adriana Heguy, Jonathan Serrano, Thomas Wisniewski, David Zagzag, Matija Snuderl, Orrin Devinsky
Content: Rationale: Patients who are candidates for epilepsy surgery or have failed epilepsy surgery are among the highest risk for sudden unexpected death in epilepsy (SUDEP) with an estimated SUDEP rate of 7-9 per 1000 patient-years. Aside from poorly controlled tonic-clonic seizures, the risk factors for SUDEP are unclear though evidence from human studies and animal models suggests a genetic contribution. In this study, we examined the genetic and epigenetic factors that may contribute to SUDEP in patients with treatment resistant focal epilepsy.Methods: Brain tissues from epilepsy surgery resections of 8 probable/definite SUDEP patients were identified based on clinical history. For methylation studies, we selected 7 control samples from patients who had undergone epilepsy surgery matched for age at surgery, sex, year of surgery and lobe of resection. Whole exome sequencing was performed using SeqCap capture (NimbleGen) and 50 base-pair paired-end sequencing. Epigenome was analyzed using genome-wide methylation array profiling (Illumina Infinium HumanMethylation 450k). Realigned exomes were queried for SNPs, HaplotypeCaller from GATK was used. High frequency SNPs found in 1000g, ESP6500 and dbSNP141 were filtered out. Resulting filtered putative mutations were annotated using ANNOVAR RefSeq hg19. Synonymous mutations were excluded. Mutations were grouped by genes and analyzed using MSigDB, IPA, Reactome and CarpeDB databases.Results: In 8 SUDEP cases, we identified 804 unique rare mutations. Of these, 690 (86%) were private to one patient, 54 (7%) were present in 2 patients, 27 (3%) in 3, 12 (1%) in 4, 8 (1%) in 5, 7(1%) in 6, 4 (<1%) in 7 and 2 (<1%) in 8 patients. Forty-six of these genes were located on chromosome 19q13 known to be associated with cardiac conduction diseases. Five patients showed unique mutations in 8 cardiac conduction disorder genes ranging from 1 up to 5 affected genes per patient. Furthermore, we identified alterations in 9 genes responsible for neurotransmission. Epigenetic profiling showed distinctly abnormal profiles of both SUDEP and non-SUDEP cortical tissue even in the absence of cortical dysplasia suggesting methylation alterations in the setting of seizures.Conclusions: SUDEP patients show unique genetic alterations associated with cardiac conduction disorders and neurotransmission. Multiplexed genetic testing for these mutations may allow early identification of patients with epilepsy who are in high risk of sudden death.