Impact of Genetic Testing on Therapeutic Decision-Making in Childhood-Onset Epilepsies-a Study in a Tertiary Epilepsy Center

We assessed the frequency of pediatric monogenic epilepsies and precision therapies at a tertiary epilepsy center. We analyzed medical records of children, born in 2006-2011 and followed at the Danish Epilepsy Center from January to December 2015; 357 patients were identified, of whom 27 without epilepsy and 35 with acquired brain damage were excluded. Of the remaining 295 children, 188 were consented for study inclusion and genetic testing. At inclusion, 86/188 had a preexisting genetic diagnosis and did not undergo further genetic testing. The 102 genetically unsolved patients underwent WES, which identified a (likely) pathogenic variant in eight patients and a highly relevant variant of unknown significance (VUS) in seven additional patients. Single nucleotide polymorphism array was performed in the remaining 87 patients and revealed no (likely) pathogenic copy number variants (CNVs). Patients with a genetic diagnosis had a significantly lower median age at seizure onset and more often had febrile seizures, status epilepticus, or neurodevelopmental impairment compared to those who remained genetically unsolved. Most common epilepsies were focal or multifocal epilepsies and developmental and epileptic encephalopathies (DDEs). Fifty-three patients, with a putative genetic diagnosis, were potentially eligible for precision therapy approaches. Indeed, genetic diagnosis enabled treatment adjustment in 32/53 (60%); 30/32 (93%) patients experienced at least a 50% reduction in seizure burden while only 4/32 (12.5%) became seizure-free. In summary, a genetic diagnosis was achieved in approximately 50% of patients with non-acquired epilepsy enabling precision therapy approaches in half of the patients, a strategy that results in > 50% reduction in seizure burden, in the majority of the treated patients.