Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

�Epileptic encephalopathiesare a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of � 9 known and 46 candidate genesfor epileptic encephalopathyin 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in � 0% of our cohort. Six of the 46 candidate geneshad � or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2and SYNGAP1mutations are new causes of epileptic encephalopathies, accounting for � .2% and � % of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathiesto undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders. Epilepsy is one of the most common neurological disorders, with a lifetime incidence rate of 3%. Epileptic encephalopathiesare a devastating group of epilepsies characterized by refractory seizures and cognitive arrest or regression, associated with ongoing epileptic activity, that typically carry a poor prognosis 1 . De novo mutationsin several genes are known to be responsible for some epileptic encephalopathies2 . Furthermore, we and others have shown that rare, de novo copy number variants (CNVs) account for up to ~8%