title: Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.
abstract: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation.
  
  
  
  To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes.
  
  
  
  Twenty-nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X-linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X-linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed-up candidate genes, and the patient's phenotype was similar to a few recent publications.
  
  
  
  Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss-of-function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life.
authors.affiliation: Department of Genetics UMC Utrecht Utrecht The Netherlands.
authors.forename: Carolien G F
authors.identifier: http://orcid.org/0000-0002-7818-1396
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: Department of Genetics UMC Utrecht Utrecht The Netherlands.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.affiliation: Department of Genetics UMC Utrecht Utrecht The Netherlands.
authors.forename: Marjan J A
authors.initials: MJ
authors.lastname: van Kempen
authors.affiliation: Department of Genetics UMC Utrecht Utrecht The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Van't Slot
authors.affiliation: Department of Genetics UMC Utrecht Utrecht The Netherlands.
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Tel Aviv Sourasky Medical Center6 Weizmann St.Tel AvivIsrael; Genetics of Epilepsy Research in Israel Tel-Aviv University Medical SchoolTel-AvivIsrael.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium; Division of NeurologyAntwerp University HospitalAntwerpBelgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Djémié
authors.affiliation: Neuroscience Department Children's Hospital Anna Meyer University of Florence Florence Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium.
authors.forename: Katia
authors.initials: K
authors.lastname: Hardies
authors.affiliation: Division of NeurologyThe Children's Hospital of PhiladelphiaPhiladephiaPennsylvania; Department of NeuropediatricsUniversity Medical Center Schleswig-HolsteinChristian Albrechts UniversityKielGermany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Neurogenetics Group Department of Molecular Genetics VIB Antwerp Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Hendrickx
authors.affiliation: Pediatric Epilepsy Unit Tel Aviv Sourasky Medical Center Tel Aviv University Tel Aviv Israel.
authors.forename: Moine
authors.initials: M
authors.lastname: Kanaan
authors.affiliation: Department of Life Sciences Bethlehem University Bethlehem Palestine.
authors.forename: Uri
authors.initials: U
authors.lastname: Kramer
authors.affiliation: Folkhälsan Institute of Genetics Neuroscience Center and Research Programs Unit Molecular Neurology University of Helsinki Helsinki Finland.
authors.forename: Anna-Elina E
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Institute of Human Genetics University of Leipzig Hospitals and Clinics Leipzig Germany.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Neuroscience Department Children's Hospital Anna Meyer University of Florence Florence Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.affiliation: Neuroscience Department Children's Hospital Anna Meyer University of Florence Florence Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.affiliation: Danish Epilepsy Centre - FiladelfiaDianalundDenmark; Institute for Regional Health ServicesUniversity of Southern DenmarkDK-5230OdenseDenmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: Department of Neuropediatrics University Medical Center Schleswig-Holstein Christian Albrechts University Kiel Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pendziwiat
authors.affiliation: Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Stamberger
authors.affiliation: Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.affiliation: Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Department of Genetics UMC Utrecht Utrecht The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
keywords: De novo; HNRNPU; X‐linked; epileptic encephalopathy; loss‐of‐function; prioritization; recessive; targeted panel sequencing