Epilepsy is one of the most common neurological disorders, affecting as many as 1 in 26 individuals. The childhood epileptic encephalopathies (CEE) are the most severe types of epilepsy, characterized by refractory seizures, cognitive arrest or regression associated with ongoing epileptic activity, and a poor prognosis. Identifying the genetic causes of CEE is the initial step toward developing more effective diagnostic tests, prognosis counseling and treatments. Despite significant advances in gene discovery in recent years, the majority of patient with CEE remain undiagnosed. Our recent work (R01NS069605) to investigate the genetic basis of epilepsy helped establish the role of copy number variants (CNVs) in CEE. More recently, we use a high-throughput targeted sequencing strategy to screen 73 known and candidate CEE genes for mutations in a cohort of >500 CEE probands, identifying pathogenic mutations in >10% of patients. Our studies identified CHD2 and SYNGAP1 as novel and important causes of CEE, GRIN2A as a cause of epilepsy-aphasia syndromes and GABRA1 and STXBP1 as causes of a subset of SCN1A- negative Dravet syndrome. In this proposal, we build upon these successes and propose three lines of investigation. First, we will extend our high-throughput screening discover additional genes for CEE and to establish the role of CEE genes in other, related neurodevelopmental disorders including intellectual disability with and without epilepsy. Second, we will investigate the role of the chromatin remodeling pathway in epileptogenesis, highlighted by the discovery of CHD2 mutations in a subset of CEE patients. Finally, we will use a series of experiments to identify the """"""""missing"""""""" mutations in Dravet syndrome, a specific type of CEE. Successful completion of our aims will lead to improved genetic diagnosis of patients, better prognosis and recurrence risk counseling for families, and novel targets for development of therapeutics.
Epilepsy is one of the most common neurological disorders in humans, affecting up to 3% of the population. Childhood epileptic encephalopathies are the most severe form of epilepsy with onset in early childhood, multiple seizure types that are difficult to treat, and poor developmenta outcomes. There is considerable evidence that genetic mutations cause childhood epileptic encephalopathies, and our recent research has identified several new genetic causes. However, most cases are still not explained. This research will identify new genes and genetic pathways in epilepsy. Furthermore, we will study the specific genetics changes disrupt normal brain function. Our results and will directly benefit individuals with epilepsy and their families throug 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.
|O'Roak, Brian J; Vives, Laura; Fu, Wenqing et al. (2012) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619-22|