title: Investigating the genetic basis of fever-associated syndromic epilepsies using copy number variation analysis.
abstract: Fever-associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A 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 (CNVs) in 36 patients with SCN1A-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 CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs 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 CNVs 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.
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Hartmann
authors.forename: Sarah
authors.initials: S
authors.lastname: von Spiczak
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.forename: Gunnar
authors.initials: G
authors.lastname: Buyse
authors.forename: Catheline
authors.initials: C
authors.lastname: Vilain
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Bogaert
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Joseph
authors.initials: J
authors.lastname: Cook
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D004827:Epilepsy / Q000209:etiology* / Q000235:genetics*; D005260:Female; D005334:Fever / Q000150:complications*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Copy number variation; Dravet syndrome; Febrile seizures plus; Fever-associated syndromic epilepsy; SCN1A-negative