title: Structural genomic variation in childhood epilepsies with complex phenotypes.
abstract: A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: 1] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands [2] SEIN Epilepsy Institute in the Netherlands Foundation, Hoofddorp, The Netherlands.
authors.forename: Marielle E M
authors.initials: ME
authors.lastname: Swinkels
authors.affiliation: Department of Medical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Emmelien
authors.initials: E
authors.lastname: Aten
authors.affiliation: Department of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Boor
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: von Spiczak
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Jähn
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Binsbergen
authors.affiliation: Department of Child Neurology, Rudolf Magnus Institute of Neurosciences, University Medical Center Utrecht, The Netherlands.
authors.forename: Onno
authors.initials: O
authors.lastname: van Nieuwenhuizen
authors.affiliation: Department of Child Neurology, Rudolf Magnus Institute of Neurosciences, University Medical Center Utrecht, The Netherlands.
authors.forename: Floor E
authors.initials: FE
authors.lastname: Jansen
authors.affiliation: Department of Child Neurology, Rudolf Magnus Institute of Neurosciences, University Medical Center Utrecht, The Netherlands.
authors.forename: Kees P J
authors.initials: KP
authors.lastname: Braun
authors.affiliation: SEIN Epilepsy Institute in the Netherlands Foundation, Hoofddorp, The Netherlands.
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: de Haan
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.affiliation: 1] Danish Epilepsy Centre, Dianalund, Denmark [2] Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
authors.affiliation: 1] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands [2] SEIN Epilepsy Institute in the Netherlands Foundation, Hoofddorp, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.affiliation: 1] Wilhelm Johannsen Centre for Functional Genome Research, Copenhagen, Denmark [2] Danish Epilepsy Centre, Dianalund, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D004827:Epilepsy / Q000000981:diagnostic imaging / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D011859:Radiography