Abstracts

Rationale: Genetic causes of epileptic encephalopathy have been increasingly uncovered with the aid of advanced sequencing technology. However, diagnostic yield of single genetic test is still low except SCN1A analysis in Dravet syndrome patient. Thus, we attempted to develop comprehensive targeted epileptic encephalopathy gene panel and validate the diagnostic yield in a large group of infantile onset epileptic encephalopathy patients Methods: Thirty two infantile onset epileptic encephalopathy patients were included. A custom in solution hybridization capture kit was designed targeting 83 epileptic encephalopathy related genes. All known and putative pathogenic variants identified from massively parallel sequencing were confirmed with Sanger sequencing. Inherited or de novo mutations were also confirmed through family study. Results: We confirmed 9 pathogenic mutations (SCN1A T199Sfs*15, c..2914-1G>A, R1407X; SCN2A F978L, K156E; KCNQ2 G256W, R333W; STXBP1 R235X; ARHGEF9 W452X). Five additional variants (SCN2A I769T; GABRA1 K339E; CHRNA4 L301M; GRIN2A P1279L; SYNGAP1 c.2116-1G>A) predicted as deleterious are now waiting for family study results. Diagnostic yield of the present targeted panel is expected to lie between 28% (9/32) to 44% (14/32). One pathogenic (ARHGEF9) and two putative (GABRA1 and CHRNA4) variants were identified in Dravet syndrome patients with no detectable SCN1A mutation Conclusions: Targeting sequencing of infantile onset epileptic encephalopathy patients resulted in genetic diagnosis of approximate one thirds of patients. This study also extended genetic spectrum of Dravet syndrome with no detectable SCN1A mutation