title: Mutations in KCNT1 cause a spectrum of focal epilepsies.
abstract: Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.
authors.affiliation: Danish Epilepsy Center, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
authors.affiliation: Amplexa Genetics, Odense, Denmark.
authors.forename: Line H G
authors.initials: LH
authors.lastname: Larsen
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Chiao Xin
authors.initials: CX
authors.lastname: Lim
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ricos
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Bayly
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Marjan J A
authors.initials: MJ
authors.lastname: van Kempen
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Klinkenberg
authors.affiliation: Neurology Service, Sydney Children's Hospital, Randwick, New South Wales, Australia.|School of Women's and Children's Health, University of New South Wales, Kensington, New South Wales, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Andrews
authors.affiliation: NorthShore University HealthSystem, Evanston, Illinois, U.S.A.
authors.forename: Kent
authors.initials: K
authors.lastname: Kelley
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Ronen
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Callen
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Simone C
authors.initials: SC
authors.lastname: Yendle
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Hospital Necker-Enfants Malades, Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.affiliation: Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, U.S.A.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genova, Italy.
authors.forename: Pasquale
authors.identifier: http://orcid.org/0000-0002-6065-1476
authors.initials: P
authors.lastname: Striano
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genova, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Baglietto
authors.affiliation: Laboratory of Neurogenetics, Department of Neurosciences, G. Gaslini Institute, Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Department of Neurology, Women's and Children's Health Network, Adelaide, South Australia, Australia.|School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Smith
authors.affiliation: Department of Neurology, Women's and Children's Health Network, Adelaide, South Australia, Australia.
authors.forename: Clair
authors.initials: C
authors.lastname: Pridmore
authors.affiliation: Danish Epilepsy Center, Dianalund, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Gardella
authors.affiliation: Danish Epilepsy Center, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Marina
authors.initials: M
authors.lastname: Nikanorova
authors.affiliation: Amplexa Genetics, Odense, Denmark.
authors.forename: Hans Atli
authors.initials: HA
authors.lastname: Dahl
authors.affiliation: Danish Epilepsy Center, Dianalund, Denmark.
authors.forename: Pia
authors.initials: P
authors.lastname: Gellert
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.|Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.|Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: SEIN - Epilepsy Institutes in the Netherlands Foundation, Zwolle, The Netherlands.
authors.forename: Boudewijn
authors.initials: B
authors.lastname: Gunning
authors.affiliation: Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Kragh-Olsen
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004828:Epilepsies, Partial / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D000081033:Potassium Channels, Sodium-Activated; D013398:Sudden Infant Death / Q000235:genetics
chemical_list: C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated
keywords: Autosomal dominant nocturnal frontal lobe epilepsy; Cardiac arrhythmia; Epileptic encephalopathy; KCNT1; Sudden unexpected death in epilepsy