Epilepsy is one of the most common neurological disorders in humans. The etiology of epilepsy is complex, with the contribution of both environmental and genetic factors. Linkage analysis and candidate gene studies have enabled the discovery of several epilepsy genes, mutations in which cause rare, autosomal dominant or sporadic forms of epilepsy. Despite these advances, for the vast majority of individuals with epilepsy, the genetic cause is unknown. Recent advances in technology now permit genome-wide analyses for both copy number and sequence changes. Unlike genome-wide studies in many neurodevelopmental disorders, there are no published genome-wide studies in epilepsy to date. The overall goal of this study is to use genomic approaches, including array comparative genomic hybridization and whole exome sequencing, to identify novel candidate genes for epilepsy. We will perform genome-wide array CGH analysis for copy number changes in a cohort of 2000 individuals with epilepsy. We will also use next- generation sequencing technology to perform exome sequencing to identify mutations in a subset of individuals with severe childhood-onset encephalopathy. Each of these whole-genome technologies offers an unbiased approach for identifying novel candidate genes and pathways for epilepsy. We will then use the results of these studies to inform selection of candidate genes for resequencing in 500 affected individuals. The discovery of novel genes and pathways in epilepsy using the genomic approaches within this proposal will further our understanding of brain development and epileptogenesis and allow better prognosis and recurrence risk counseling for families.

Public Health Relevance

Epilepsy is one of the most common neurological disorders in humans, affecting up to 3% of the population. Although it is clear that there is a strong genetic component for epilepsy, there are still only a few genes known. This research will identify new genes and genetic pathways in epilepsy and will directly benefit individuals with epilepsy and their families through improved diagnostic, prognostic and recurrence risk information. Greater understanding of the genes involved in normal development and function of the brain will facilitate improved therapies for this common disorder and benefit society as a whole.

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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University of Washington
Schools of Medicine
United States
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Epi4K Consortium. Electronic address: epi4k@columbia.edu; Epi4K Consortium (2016) De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. Am J Hum Genet 99:287-98
EpiPM Consortium (2015) A roadmap for precision medicine in the epilepsies. Lancet Neurol 14:1219-28
Hartmann, Corinna; von Spiczak, Sarah; Suls, Arvid et al. (2015) Investigating the genetic basis of fever-associated syndromic epilepsies using copy number variation analysis. Epilepsia 56:e26-32
Mefford, Heather C; Zemel, Matthew; Geraghty, Eileen et al. (2015) Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology 85:756-62
Larsen, Jan; Carvill, Gemma L; Gardella, Elena et al. (2015) The phenotypic spectrum of SCN8A encephalopathy. Neurology 84:480-9
Carvill, Gemma L; McMahon, Jacinta M; Schneider, Amy et al. (2015) Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Am J Hum Genet 96:808-15
Watson, Corey T; Marques-Bonet, Tomas; Sharp, Andrew J et al. (2014) The genetics of microdeletion and microduplication syndromes: an update. Annu Rev Genomics Hum Genet 15:215-44
Carvill, Gemma L; Weckhuysen, Sarah; McMahon, Jacinta M et al. (2014) GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 82:1245-53
Carvill, Gemma L; Heavin, Sinead B; Yendle, Simone C et al. (2013) Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 45:825-30
Mullen, Saul A; Carvill, Gemma L; Bellows, Susannah et al. (2013) Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 81:1507-14

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