Abstracts

Rationale: Microdeletions at 15q11.2, 15q13.3 and 16p13.11 are known genetic risk factors for the Idiopathic Generalized Epilepsies and other neurodevelopmental disorders including intellectual disability, autism and schizophrenia. While some of these microdeletions have also been described in other epilepsy syndromes, the full phenotypic range of this microdeletion triad in pediatric epilepsies is unknown. We attempted to describe the range of associated phenotypes of 15q11.2, 15q13.3 and 16p13.11 microdeletions in a diverse cohort of pediatric epilepsy patients. Methods: We screened a diverse cohort of 570 patients with pediatric epilepsies for microdeletions at 15q11.2, 15q13.3 and 16p13.11 using quantitative polymerase chain reaction. The cohort included 101 patients with Idiopathic Generalized Epilepsies, 20 patients with idiopathic focal epilepsies, 126 patients with fever-associated epilepsy syndromes including Febrile Seizures (FS), Febrile Seizures Plus (FS+) and Genetic Epilepsy with Febriles Seizures Plus (GEFS+), 201 patients with other diverse epilepsy syndromes including Dravet Syndrome, symptomatic and cryptogenic focal epilepsies and unclassified epilepsies as well as cohort of 122 children with single unclassified seizures or epilepsy-associated EEG patterns without seizures. 131/571 patients (22.9%) had mild, moderate or severe intellectual disability (ID). Identified microdeletions were confirmed using array comparative hybridization. Detailed phenotyping was performed in microdeletion carriers. Results: Eight microdeletions in 15q11.2 (n=2), 15q13.3 (n=3) and 16p13.11 (n=3) were identified in the overall cohort of 571 probands. 7/8 microdeletions were identified in patients with IGE (5/101, 4.9%) or patients with generalized EEG patterns without seizures (2/122, 1.6%) including generalized spike-wave (GSW) and photoparoxymal response (PPR). No microdeletions were identified in patients with FS, FS+ or GEFS+. In the cohort of 201 patients with other diverse epilepsy syndromes, a single 15q11.2 microdeletion was identified in a patient with cryptogenic focal epilepsy and PPR grade IV. 5/8 microdeletion carriers had various degrees of ID; the frequency of microdeletions in patients with epilepsy and ID was higher (3.8%) compared to epilepsy patients with normal intellect (0.7%). Iterative phenotyping revealed a wide range of generalized epilepsy phenotypes associated with these microdeletions not easily classifiable using the standard ILAE nomenclature.Conclusions: Recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 are exclusively associated with a wide range of phenotypes related to idiopathic generalized epilepsies or related EEG patterns such as GSW and PPR. These recurrent microdeletions are virtually absent in focal epilepsies, FS, FS+ and GEFS+. Microdeletion carriers have a six-fold risk to present with various degrees of ID compared to patients without these risk factors. This microdeletion triad might help delineate a novel spectrum of epilepsy phenotypes classifiable through clinical, electrographic and genetic data.