(Hawkins, et. al. 2016). Because two people with the same SCN1A mutation can present with substantially different symptoms, often at opposite ends of the spectrum, scientists know there must be modifiers that affect how SCN1A mutations manifest in clinical severity. In fact, creating a Dravet syndrome mouse line is not as simple as inserting a particular mutation or even knocking out an SCN1A gene in the mice: A particular mutation can have a normal presentation or a Dravet-like presentation depending on which strain of mouse it is expressed in or crossed with. By looking at the genetic differences between two such strains, the scientists identified several potential Dravet syndrome modifiers. The scientists then examined these modifiers and how they were expressed using RNA-seq, finding that a specific receptor subunit, Gabra2, was expressed differently between the mouse strains. The fact that clobazam (which is known to act on the Gabra2 receptor) protects against heat-induced seizures in the SCN1A +/- mice supports the theory that Gabra2 may be a genetic modifier in this mouse model.

Hawkins, N.A., et. Al. (2016). Fine mapping of a Dravet syndrome modifier locus on mouse chromosome 5 and candidate gene analysis by RNA-seq. PLoS Genetics. Oct 21;12(10). Doi: 10.1371/journal.pgen.1006398.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074504/