Duplications of 17q12 can cause familial fever-related epilepsy syndromes

Objectives: After we identified a 17q12 duplication cosegregating in a 4-generation family with genetic or generalized epilepsy with febrile seizures plus (GEFS+), we aimed to determine the frequency of 17q12 genomic rearrangements in GEFS+ and a wide spectrum of other epilepsy phenotypes. We furthermore describe seizure prevalence in previously reported patients with a 17q12 duplication or deletion. Methods: We analyzed 433 patients with a broad range of epilepsy phenotypes. The 180k Cytosure ISCA v2 array was used for copy number variation screening in the index patient. Segregation analysis and follow-up studies were performed with the multiplex amplicon quantification technique. Results: We identified 2 families in which a 17q12 duplication segregated with febrile-sensitive epilepsy. In the follow-up study, the mutation rate in familial febrile seizures (FS) and GEFS+ phenotypes was 1/222. No 17q12 deletions were detected. Two of the 6 mutation carriers in the initial GEFS+ family had mild intellectual disability, whereas all family members of the second family were of normal intelligence. In the literature, 4 of 43 individuals with a 17q12 duplication and 4 of 55 with the reciprocal deletion were described to have had seizures. Conclusions: Our study shows that 17q12 duplications are a rare cause of familial FS and GEFS+. Although some family members might have intellectual disability, seizures can be the sole clinical symptom. This is the first report on an inherited copy number variation in these self-limiting fever-sensitive epilepsy syndromes, potentially revealing a novel pathomechanism involved in familial FS and GEFS+.