Abstracts

Rationale: Dravet syndrome (DS) is an epileptic encephalopathy of infantile onset caused by SCN1A mutations or microdeletions. There is considerable variability among individuals carrying the same primary mutation, suggesting that clinical outcome may be modulated by variants at other genes. Methods: To identify modifier gene variants that contribute to clinical outcome we sequenced the exomes of 10 mildly affected and 12 severely affected individuals with a de novo truncation mutation in SCN1A. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes, and 3) rare variants in 237 candidate genes associated with neuronal excitability. Results: We found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 severely affected individuals. Interestingly, exomes from healthy individuals have a similar prevalence of rare damaging variants as severely affected individuals in these neuronal excitability genes. Conclusions: Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.  Funding: Dravet Syndrome Foundation grant to MFH and SH