Dravet syndrome-associated mutations in , and define the genetic landscape of defects of GABA receptors.

Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic-clonic seizures followed by status epilepticus. variants in genes that mediate synaptic transmission such as and are often associated with Dravet syndrome. Recently, GABA receptor subunit genes () encoding α1 (), β3 () and γ2 (), but not β2 () or β1 (), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different . Interestingly, the variants were all in genes encoding the most common GABA receptor, the α1β2γ2 receptor. Mutations in (c.644T>C, p. L215P; c.640C>T, p. R214C; c.859G>A; V287I; c.641G>A, p. R214H) and (c.269C>G, p. T90R; c.1025C>T, p. P342L) presented as cases, while in two variants were (c.992T>C, p. F331S; c.542A>T, p. Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these variants on GABA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of and Dravet syndrome variants, while mainly trafficking defects were found with the (c.269C>G, p. T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these variants are all targeting genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.