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Investigating the genetic basis of fever‐associated syndromic epilepsies using copy number variation analysis
Author(s) -
Hartmann Corinna,
Spiczak Sarah,
Suls Arvid,
Weckhuysen Sarah,
Buyse Gunnar,
Vilain Catheline,
Van Bogaert Patrick,
De Jonghe Peter,
Cook Joseph,
Muhle Hiltrud,
Stephani Ulrich,
Helbig Ingo,
Mefford Heather C.
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12920
Subject(s) - dravet syndrome , copy number variation , proband , epilepsy , febrile seizure , comparative genomic hybridization , epilepsy syndromes , gene duplication , medicine , autism , genetics , biology , pediatrics , mutation , psychiatry , chromosome , genome , gene
Summary Fever‐associated syndromic epilepsies ranging from febrile seizures plus ( FS +) to Dravet syndrome have a significant genetic component. However, apart from SCN 1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome‐wide screening for copy number variations ( CNV s) in 36 patients with SCN 1A ‐negative fever‐associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever‐associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 × 180K arrays. We identified 13 rare CNV s in 8 (22%) of 36 individuals. These included known pathogenic CNV s in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS +, and two deletions at 16p11.2 and 1q44 in two individuals with fever‐associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS + and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNV s were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever‐associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes.