Abstracts

Rationale: Whole exome studies in patients with epileptic encephalopathies (EE) have demonstrated the breadth of genetic heterogeneity in these severe childhood epilepsy syndromes. Our previous study identified 329 de novo mutations in 305 genes when 264 trios (affected child and unaffected parents) were sequenced. We aimed to identify additional patients with de novo mutations in 27 of these candidate genes to confirm the role of each gene in EE and to further define the phenotypic spectrum.Methods: We performed targeted capture and high-throughput resequencing of 27 genes in which a de novo mutation was identified in one or more proband with Infantile Spasms (IS) or Lennox-Gastaut syndrome (LGS) in our prior study. 537 patients with diverse EE phenotypes were screened.Results: We identified 16 patients with de novo mutations in 7 genes, thus establishing a genetic diagnosis for ~3% of our cohort. Among these are recurrent and novel mutations in ALG13, CACNA1A, DNM1, GABRB3, GNAO1, IQSEC2, and SLC1A2 highlighting the importance of these genes in EE. Notably, recurrent mutations accounted for 44% of the pathogenic variants identified in this study. For two independent families with multiple affected individuals, we identified a parent with a mosaic germline mutation. GABRB3 accounted for the majority of pathogenic variants (n=6/537), explaining ~1% of our cohort. We will report the frequency of de novo mutations for each gene screened in our cohort as well as investigate genotype-phenotype correlations for genes in which multiple patients harbor mutations.Conclusions: We have confirmed the role of at least 7 additional genes in the genetic etiology of EE and expanded the phenotypic spectrum associated with these genes beyond IS and LGS in which they were first discovered.