Molecular Genetics of Dravet Syndrome

Abstract Dravet syndrome is a severe epilepsy disorder characterised by infantile onset of fever‐sensitive seizures. Seizures are therapy resistant, and although children develop normal in the first year of life, progressive cognitive decline occurs soon after seizure onset. Dravet syndrome has a genetic etiology and mutations in the sodium channel α1 subunit gene ( SCN1A ) are found in approximately 70% of patients. Most mutation occur de novo , although some familial SCN1A mutations have been reported. A small percentage of female patients with a phenotype resembling Dravet syndrome have a mutation in the protocadherin 19 gene ( PCDH19 ) on the X‐chromosome. Rare mutations have been found in a few other ion channel genes, but still the genetic cause of approximately 20% of patients with Dravet syndrome remains unknown. Key Concepts: Dravet syndrome is the most frequent indication for DNA analysis within the group of epileptic encephalopathies. In approximately 70% of patients with Dravet syndrome, a heterozygous dominant de novo mutation in SCN1A can be identified. In patients with a clinical diagnosis of Dravet syndrome who test negative for SCN1A sequence‐based mutations, additional tests that are capable of detecting copy number variations such as MAQ, MLPA or aCGH are required as SCN1A whole gene or exonic deletions/duplications can be missed on Sanger sequencing. SCN1A mutations in Dravet syndrome lead to haploinsufficiency of the gene. Dravet syndrome is at the most severe end of the GEFS+ spectrum. SCN1A germline and somatic mosaicisms are important causes of recurrence of Dravet syndrome within siblings and intrafamilial clinical heterogeneity. In 25% of female patients with Dravet syndrome who test negative for SCN1A mutations a PCDH19 mutation can be found. In 20% of patients with Dravet syndrome the etiology remains unknown after diagnostic testing of all relevant genes.