Our data incriminate defective ion channels co-expressed in heart and brain as important molecular risk factors for sudden unexpected death in epilepsy (SUDEP). We propose a novel array-based analysis of candidate SUDEP genes in samples from SUDEP cases and their families. This proposal complements our ongoing work in support of our central hypothesis: """"""""Mutations in ion channel genes co-expressed in heart and brain underlie the phenotype of cardiac arrhythmias and seizures and may ultimately lead to SUDEP."""""""" Many idiopathic cardiac arrhythmias in the young are linked to channelopathies and mutations of ion channel genes are recognized causes of epileptogenicity. SUDEP is a catastrophic complication of epilepsy of unknown cause. The literature-based evidence and mouse model data originating from our laboratory indicate that defective ion channels co-expressed in heart and brain are important molecular risk factors for SUDEP. We performed a feasibility study on a cohort of 47 patients with epilepsy and analyzed several SUDEP cases using our custom built ion channel gene-specific comparative hybridization array (ICCH array) interrogating over 250 ion channel subunits, including all main cardiac arrhythmia genes. We identified copy number variants (CNVs) which may play a critical role in the SUDEP pathophysiology. Based on these positive pilot results I propose using our ICCH platform to analyze samples from SUDEP families for CNVs in (1) all major ion channel subunit genes known to be associated with inherited malignant cardiac arrhythmias, (2) in all non-arrhythmia ion channel genes, and (3) to map mutant novel ion channel genes identified in aim 2 within the neuro-cardiac axis. In addition, I have laid ground work for the development of the first centralized publicly accessible SUDEP repository of high quality fresh frozen SUDEP samples by working with the NIH Coriell Repository. I expect to find many variants leading to the discovery of novel genes and a better understanding of molecular mechanisms of SUDEP and definition of a gene profile of the epilepsy population at risk. Our discoveries will be of clinical use in the initiation of preventative strategies in SUDEP.

Public Health Relevance

We used novel array based analysis to identify structural mutations, copy number variations (CNVs), in neuro-cardiac ion channel genes, candidate molecular risk factors for sudden unexpected death in epilepsy (SUDEP). Our very important pilot data indicate that the proposed research will lead to better understanding of the SUDEP biology, definition of patients at risk for SUDEP, and initiation of preventative strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Whittemore, Vicky R
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Baylor College of Medicine
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United States
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Goldman, Alica M; Behr, Elijah R; Semsarian, Christopher et al. (2016) Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention. Epilepsia 57 Suppl 1:17-25
Goldman, Alica M (2015) Mechanisms of sudden unexplained death in epilepsy. Curr Opin Neurol 28:166-74
Klassen, Tara L; Bomben, Valerie C; Patel, Ankita et al. (2014) High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. Epilepsia 55:e6-12
Klassen, Tara L; Drabek, Janice; Tomson, Torjborn et al. (2013) Visual automated fluorescence electrophoresis provides simultaneous quality, quantity, and molecular weight spectra for genomic DNA from archived neonatal blood spots. J Mol Diagn 15:283-90
Klassen, Tara L; von RĂ¼den, Eva-Lotta; Drabek, Janice et al. (2012) Comparative analytical utility of DNA derived from alternative human specimens for molecular autopsy and diagnostics. J Mol Diagn 14:451-7