(Hammer MF, et al. 2017) There is a broad spectrum of severity in Dravet syndrome, even among patients who have the same SCN1A mutation, which suggests other genes may play a role in modifying the clinical outcome. Mouse lines with a specific mutation can exhibit differing severities depending on the strain of mouse with which they are bred.
In this study, the researchers took a statistical approach and looked at whole exomes (whole library of genes) of 22 patients with Dravet syndrome and de novo SCN1A mutations at the mild end of the spectrum and the severe end of the spectrum. Twelve severely affected patients (with IQ less than 24), and twelve mildly affected patients (with IQ between 50 and 85) were chosen for participation. Two of the mildly affected patients were categorized as GEFS+ and FS+, two were borderline DS, and the youngest members of the group progressed to the moderately and severely affected category during the study. To reduce SCN1A variability, the severe group was limited to those with truncating mutations.
The authors took three approaches: 1) They looked for common variants, or SNPs, found in the general population without epilepsy, and tried to determine if any of these was associated with mild or severe outcome. They found a correlation only between areas that did not code for functional proteins. 2) They looked for commonalities among variants near genes associated with clinical outcome. In this test, they found that FKBP5, a gene involved in the glucocorticoid receptor pathway, was associated with the severe group as long as gender was also considered. 3) Lastly, they looked for rare variants in 237 genes that are known to be associated with neuronal excitability. Here, they found that the severely affected patients carried more damaging variants than the mildly affected patients, but no single gene was identified as a modifier. Instead, it appears to be a “constellation of rare variants in an individual’s genetic background” that contributes to a more severe outcome. Interestingly, although there was a difference in this area between the mildly affected group and the severely affected group, there was no statistical difference between the severely affected group and healthy individuals, suggesting that the mildly affected patients have a reduced mutational load.