Molecular genetics of Dravet syndrome

Abstract

Before the advent of molecular genetics, the nature of Dravet syndrome remained largely obscure, and arguments in favour of either an acquired origin, such as the occurrence of Dravet syndrome after vaccination, or an inherited origin, such as the occurrence of epilepsy in relatives, were formulated. In 2001 we demonstrated that the majority of Dravet patients have a genetic cause due to loss‐of‐function mutations in the SCN1A gene. Understandably, since this syndrome severely affects reproductive fitness, these mutations almost exclusively arise de novo, with the rare exceptions of mosaic mutations in a non‐affected transmitting parent. Besides classical Sanger sequencing, mutation analysis of the SCN1A gene also requires a method that allows the detection of genomic rearrangements (MAQ, MLPA), since microdeletions or whole gene deletions also result in Dravet syndromes. Depending on the series reported and their recruitment strategies, the yield of SCN1A mutations detected varied from 50 to 80%, implying that other genes or factors must be involved in these ‘SCN1A‐negative Dravet patients’. Recently mutations in some other genes have been described in these genuine Dravet patients who do not carry an SCN1A mutation. The second most important Dravet‐associated gene is PCDH19.These patients initially may have all characteristics of Dravet syndrome but may later run a somewhat different course.