Abstracts

Rationale: Epilepsy with Myoclonic Atonic Seizures (EMAS), also known as Doose syndrome, is a rare epilepsy syndrome accounting for 1 to 2% of all childhood-onset epilepsies. EMAS has been shown to have an underlying genetic component, however the genetics of this disorder is not yet well understood. Several genes have been associated with EMAS, including SCN1A, SCN1B, GABRG2, CHD2, SLC2A1, and SLC6A1. Methods: A retrospective chart review was conducted for 77 patients evaluated at Children’s Hospital Colorado who had a suspected diagnosis of EMAS at some point in their course. Genetic testing and pertinent biochemical testing was reviewed, including microarray, mtDNA, single gene testing, epilepsy panels and whole exome sequencing (WES). For panel testing, we noted whether key genes felt to be associated with EMAS were included in the analysis. For variants of uncertain significance (VUS), results of parental testing were also noted. Family history data was collected to assess whether familial variants had been inherited from symptomatic or asymptomatic individuals. Results: 77 patients were identified, with 79% having a final diagnosis of EMAS, 10% LGS, … (see abstract by Eschbach for additional details). Overall, 77% of our cohort (59/77) had at least one genetic test performed, and a molecular diagnosis was reached for five (8.5%). 56% of patients had some family history of epilepsy or febrile seizures. Of the 72 patients (93.5%) who had biochemical testing, only one had abnormal results which prompted additional studies (elevated 3-MGA followed by a methylglutaconic aciduria panel, which was normal). Thirty-seven patients (48%) had a microarray, 5 (13.5%) of which identified a copy number variant. Only one was felt to contribute to the patient’s phenotype (a 2p16.3 deletion including NRXN1). Six patients (8%) had mtDNA testing, all of which was unremarkable. Fifty-one (66%) had an epilepsy panel, only 2 of which were positive (a likely pathogenic variant in SCN1A and a pathogenic variant in GABRG2). An additional 4 panels were significant for a VUS in an EMAS-associated gene (3 in GABRG2, 1 in SCN1B). Three of these were inherited from an asymptomatic parent. Seventeen patients (22%) had single gene testing, most commonly for SCN1A, SLC2A1, and POLG1, none of which yielded abnormal results. Of the 53 patients who had SCN1A testing through single gene or panel testing, only one was found to have a mutation. Of the six patients who had WES, two were negative, one was found to have a pathogenic variant in CHD2, one had a likely pathogenic variant in CSNK2A1, one had compound heterozygous variants in PIGN, and one had VUS in NIPA1, SZT2, and FAH, none of which were felt to fully explain the phenotype. Conclusions: While EMAS is widely accepted to have a strong genetic component, the diagnostic yield of biochemical and genetic testing is low. This may be because several genes now thought to be associated with EMAS are not included on or have only recently been added to the more commonly ordered epilepsy panels. It is also likely that there are additional causative genes yet to be discovered. Funding: N/A