title: Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion.
abstract: Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single-center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole-exome sequencing (WES), targeting a list of 137 epilepsy-associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible. Infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We identified disease-causing variants in 11 children (22%) in the following genes: STXBP1 (n = 3), KCNB1 (n = 2), KCNT1, SCN1A, SCN2A, GRIN2A, DNM1, and KCNA2. We also identified two further variants (in GRIA3 and CPA6) in two children requiring further investigation. Eleven variants were de novo, and in one paternal testing was not possible. Phenotypes were broadened for some variants identified. This study demonstrates that WES is a clinically useful screening tool for previously investigated unexplained EOEE and allows for reanalysis of data as new genes are being discovered. Detailed phenotyping allows for expansion of specific gene disorders leading to epileptic encephalopathy and emerging sub-phenotypes.
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Allen
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.|Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Judith
authors.initials: J
authors.lastname: Conroy
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.
authors.forename: Amre
authors.initials: A
authors.lastname: Shahwan
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.
authors.forename: Bryan
authors.initials: B
authors.lastname: Lynch
authors.affiliation: Laboratory of Clinical Genomics, Faculty of Medicine of Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Raony G
authors.initials: RG
authors.lastname: Correa
authors.affiliation: Laboratory of Clinical Genomics, Faculty of Medicine of Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Sergio D J
authors.initials: SD
authors.lastname: Pena
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.|Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Dara
authors.initials: D
authors.lastname: McCreary
authors.affiliation: Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.|The National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland.
authors.forename: Tiago R
authors.initials: TR
authors.lastname: Magalhães
authors.affiliation: Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Lynch
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.|Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Mary D
authors.initials: MD
authors.lastname: King
mesh_terms: D059472:Exome / Q000502:physiology*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012189:Retrospective Studies; D013036:Spasms, Infantile / Q000175:diagnosis* / Q000235:genetics*
keywords: encephalopathy; epilepsy; infantile spasms