Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures

Snezana Maljevic; Sabina Vejzovic; Matthias K Bernhard; Astrid Bertsche; Sebastian Weise; Miriam Döcker; Holger Lerche; Johannes R Lemke; Andreas Merkenschlager; Steffen Syrbe

doi:10.1159/000447461

Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures

Mol Syndromol. 2016 Sep;7(4):189-196. doi: 10.1159/000447461. Epub 2016 Jul 7.

Affiliations

¹ 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.
² Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Heidelberg, Germany.
³ Department of Women and Child Health, Hospital for Children and Adolescents, Heidelberg, Germany.
⁴ CeGaT GmbH, Tübingen, University Hospital Heidelberg, Heidelberg, Germany.
⁵ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
⁶ 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.

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 by KCNQ2 and KCNQ3. While most BFNS families carry alterations in KCNQ2, mutations in KCNQ3 appear to be less common. Here, we describe a family with 6 individuals presenting with neonatal focal and generalized seizures. Genetic testing revealed a novel KCNQ3 variant, 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 in Xenopus laevis oocytes 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.

Keywords: Familial neonatal convulsions; KCNQ2; KCNQ3; Levetiracetam; Neonatal seizures; Potassium channels.