title: NovelKCNQ3Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures.
abstract: Benign familial neonatal seizures (BFNS) present a rare familial epilepsy syndrome caused by genetic alterations in the voltage-gated potassium channels Kv7.2 and Kv7.3, encoded byKCNQ2andKCNQ3.While most BFNS families carry alterations inKCNQ2, mutations inKCNQ3appear to be less common. Here, we describe a family with 6 individuals presenting with neonatal focal and generalized seizures. Genetic testing revealed a novelKCNQ3variant, c.835G>T, cosegregating with seizures in 4 tested individuals. This variant results in a substitution of the highly conserved amino acid valine localized within the pore-forming transmembrane segment S5 (p.V279F). Functional investigations inXenopus laevisoocytes revealed a loss of function, which supports p.V279F as a pathogenic mutation. When p.V279F was coexpressed with the wild-type (WT) Kv7.2 subunits, the resulting potassium currents were about 10-fold reduced compared to the WT Kv7.3 and Kv7.2 coexpression. Genotype-phenotype correlation shows an incomplete penetrance of p.V279F. Response to antiepileptic treatment was variable, but evaluation of treatment response remained challenging due to the self-limiting character of the disease. The identification of the pathogenic variant helped to avoid unnecessary investigations in affected family members and allowed guided therapy.
authors: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Heidelberg, Germany; The Florey Institute of Neuroscience and Mental Health, Melbourne, Vic., Australia.
authors: Snezana
authors: S
authors: Maljevic
authors: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Heidelberg, Germany.
authors: Sabina
authors: S
authors: Vejzovic
authors: Department of Women and Child Health, Hospital for Children and Adolescents, Heidelberg, Germany.
authors: Matthias K
authors: MK
authors: Bernhard
authors: Department of Women and Child Health, Hospital for Children and Adolescents, Heidelberg, Germany.
authors: Astrid
authors: A
authors: Bertsche
authors: Department of Women and Child Health, Hospital for Children and Adolescents, Heidelberg, Germany.
authors: Sebastian
authors: S
authors: Weise
authors: CeGaT GmbH, Tübingen, University Hospital Heidelberg, Heidelberg, Germany.
authors: Miriam
authors: M
authors: Döcker
authors: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Heidelberg, Germany.
authors: Holger
authors: H
authors: Lerche
authors: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors: Johannes R
authors: JR
authors: Lemke
authors: Department of Women and Child Health, Hospital for Children and Adolescents, Heidelberg, Germany.
authors: Andreas
authors: A
authors: Merkenschlager
authors: Department of Women and Child Health, Hospital for Children and Adolescents, Heidelberg, Germany; Division of Child Neurology and Inherited Metabolic Diseases, Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
authors: Steffen
authors: S
authors: Syrbe
keywords: Familial neonatal convulsions; KCNQ2; KCNQ3; Levetiracetam; Neonatal seizures; Potassium channels