The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel Na(V)1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the Na(V)1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of Na(V)1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

Automated summary

Variants of the SCN1A gene are responsible for over 85% of Dravet syndrome cases, but are now being observed in a range of other epilepsy phenotypes with increased availability of genetic testing. While most epilepsy-associated variants in SCN1A cause loss of channel function, there is a subset of missense mutations that result in increased excitability, complicating precision pharmacotherapy for patients with SCN1A variants and epilepsy. The L1624Q variant described in this study is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy, and its biophysical analysis shows a mix of gain and loss-of-function properties in SCN1A-related epilepsy.