Two autopsy cases of sudden unexpected death from Dravet syndrome with novel de novo SCN1A variants

Abstract Aim Dravet syndrome (DS) is characterized by high epilepsy-related premature mortality with a markedly young age at death, however, autopsy report of sudden unexpected death with DS has been fewer than expected. Methods We report two autopsy cases with sudden unexpected death from DS. Case 1 was a 13-year-old male who drowned in a bathtub, and Case 2 was a 3-year-old female who died while sleeping. In Case 1, the blood concentration of the anticonvulsant, valproic acid, was below the recommended therapeutic range. Neuropathological investigation and genetic analysis of 402 cardiovascular disease-related and 146 epilepsy-related genes by next generation sequencing were applied. Results No significant neuronal loss with gliosis was observed in the brain of either patient. Although possible mild malformations of cortical development were found in both, the degree thereof was similar to that of age-matched controls. Genetic analysis identified a novel variant in SCN1A intron 23 (c.4477-3T > C) in Case 1 that falls outside of the minor splicing consensus sequence. In vitro splicing functional assays with minigene constructs revealed that this intronic variant leads to a 2-bp insertion immediately before exon 24 that results in protein truncation. Similarly, a novel de novo missense mutation of unknown significance, SCN1A_Arg187Pro, was identified in Case 2. In both cases, we also identified cardiomyopathy-related variants classified as likely pathogenic; however, the effect of these variants at death was minimal because there was an absence of pathological change indicating inherited cardiomyopathy. Conclusion The present cases emphasize the need for multifaceted examination of DS cases so as to obtain a definitive autopsy diagnosis and to explore the mechanism of sudden unexpected death.