Duplications of 17q12 can cause familial fever-related epilepsy syndromes.
OBJECTIVE
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+.
From the Neurogenetics Group (K.H., S.W., P.H., P.D.J., A.S.), Department of Molecular Genetics, VIB, Antwerp; Laboratory of Neurogenetics (K.H., S.W., P.H., P.D.J., A.S.), Institute Born-Bunge, University of Antwerp; Department of Neurology (E.P., W.V.P.), University Hospital Gasthuisberg, Leuven; Center for Human Genetics (H.V.E.), University Hospitals Leuven, KU Leuven; and Division of Neurology (P.D.J.), Antwerp University Hospital, Antwerp, Belgium.
Katia
K
Hardies
Sarah
S
Weckhuysen
Elke
E
Peeters
Philip
P
Holmgren
Hilde
H
Van Esch
Peter
P
De Jonghe
Wim
W
Van Paesschen
Arvid
A
Suls
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004827:Epilepsy; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009030:Mosaicism; D059645:Mutation Rate; D010375:Pedigree; D010641:Phenotype; D003294:Seizures, Febrile / Q000235:genetics*; D058496:Smith-Magenis Syndrome; D013577:Syndrome; D014314:Trisomy / Q000235:genetics*