{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:24:04Z","timestamp":1791480244584,"version":"4.3.4"},"reference-count":66,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T00:00:00Z","timestamp":1615334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005941","name":"Dietmar Hopp Stiftung","doi-asserted-by":"publisher","award":["1DH1813319"],"award-info":[{"award-number":["1DH1813319"]}],"id":[{"id":"10.13039\/501100005941","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)\u2013valine(406)\u2013proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype\u2013phenotype correlation, variability, and predicted functional impact of KCNA2 variants.<\/jats:p>","DOI":"10.3390\/ijms22062824","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T13:27:20Z","timestamp":1615382840000},"page":"2824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders"],"prefix":"10.3390","volume":"22","author":[{"given":"Jan H.","family":"D\u00f6ring","sequence":"first","affiliation":[{"name":"Division of Paediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4231-887X","authenticated-orcid":false,"given":"Julian","family":"Schr\u00f6ter","sequence":"additional","affiliation":[{"name":"Division of Paediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"J\u00fcngling","sequence":"additional","affiliation":[{"name":"Praxis f\u00fcr Humangenetik T\u00fcbingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Biskup","sequence":"additional","affiliation":[{"name":"Praxis f\u00fcr Humangenetik T\u00fcbingen, 72076 Tuebingen, Germany"},{"name":"CEGAT GmbH, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1601-5384","authenticated-orcid":false,"given":"Kerstin A.","family":"Klotz","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"},{"name":"Department of Epileptology, Medical Center, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bast","sequence":"additional","affiliation":[{"name":"Medical Faculty, University Hospital Freiburg, 79085 Freiburg, Germany"},{"name":"Epilepsy Center Kork, Medical Faculty of the University of Freiburg, 77694 Kehl, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Dietel","sequence":"additional","affiliation":[{"name":"Epilepsy Center Kork, Medical Faculty of the University of Freiburg, 77694 Kehl, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Christoph","family":"Korenke","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital, Klinikum Oldenburg, 26133 Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Christoph","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital, Klinikum Oldenburg, 26133 Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-0003","authenticated-orcid":false,"given":"Heiko","family":"Brennenstuhl","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Rubboli","sequence":"additional","affiliation":[{"name":"Danish Epilepsy Centre, 4293 Dianalund, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9664-1448","authenticated-orcid":false,"given":"Rikke S.","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Danish Epilepsy Centre, 4293 Dianalund, Denmark"},{"name":"Department of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetan","family":"Lesca","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Lyon University Hospital, University of Lyon, 69100 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Chaix","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Children\u2019s Hospital, Purpan University Hospital, 31300 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00f6lker","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6593-896X","authenticated-orcid":false,"given":"Georg F.","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4435-6610","authenticated-orcid":false,"given":"Johannes R.","family":"Lemke","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany"},{"name":"Center for Rare Diseases, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Syrbe","sequence":"additional","affiliation":[{"name":"Division of Paediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.femsre.2005.03.003","article-title":"Prokaryotic K(+) channels: From crystal structures to diversity","volume":"29","author":"Kuo","year":"2005","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_2","first-page":"221","article-title":"Molecular evolution of voltage-sensitive ion channel genes: On the origins of electrical excitability","volume":"10","author":"Strong","year":"1993","journal-title":"Mol. Biol. Evol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1212\/WNL.0000000000003309","article-title":"Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy","volume":"87","author":"Corbett","year":"2016","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1126\/science.1086998","article-title":"A conserved domain in axonal targeting of Kv1 (Shaker) voltage-gated potassium channels","volume":"301","author":"Gu","year":"2003","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14329","DOI":"10.1523\/JNEUROSCI.4833-08.2008","article-title":"Cell-type-dependent molecular composition of the axon initial segment","volume":"28","author":"Lorincz","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14882","DOI":"10.1074\/jbc.M109.068486","article-title":"Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker: Evaluation of cardioprotective effects of kappaM-conotoxins","volume":"285","author":"Chen","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1007\/s00018-015-1948-5","article-title":"Structure of potassium channels","volume":"72","author":"Kuang","year":"2015","journal-title":"Cell Mol. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.neuron.2004.12.047","article-title":"Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores","volume":"45","author":"Tombola","year":"2005","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11352","DOI":"10.1073\/pnas.1000142107","article-title":"Structure of the full-length Shaker potassium channel Kv1.2 by normal-mode-based X-ray crystallographic refinement","volume":"107","author":"Chen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1126\/science.1116269","article-title":"Crystal structure of a mammalian voltage-dependent Shaker family K+ channel","volume":"309","author":"Long","year":"2005","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3389\/fnsyn.2020.00013","article-title":"Stereotactically Injected Kv1.2 and CASPR2 Antisera Cause Differential Effects on CA1 Synaptic and Cellular Excitability, but Both Enhance the Vulnerability to Pro-epileptic Conditions","volume":"12","author":"Kirschstein","year":"2020","journal-title":"Front. Synaptic. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2290","DOI":"10.1212\/WNL.0000000000009523","article-title":"CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension","volume":"94","author":"Syrbe","year":"2020","journal-title":"Neurology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ng.3239","article-title":"De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy","volume":"47","author":"Syrbe","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1111\/cge.12542","article-title":"Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: Proposal for a new channelopathy","volume":"87","author":"Pena","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Helbig, K.L., Hedrich, U.B., Shinde, D.N., Krey, I., Teichmann, A.C., Hentschel, J., Schubert, J., Chamberlin, A.C., Huether, R., and Lu, H.M. (2016). A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia. Ann. Neurol., 80.","DOI":"10.1002\/ana.24762"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1093\/brain\/awx184","article-title":"Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies","volume":"140","author":"Masnada","year":"2017","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1093\/brain\/awz195","article-title":"Incidence and phenotypes of childhood-onset genetic epilepsies: A prospective population-based national cohort","volume":"142","author":"Symonds","year":"2019","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1111\/epi.13250","article-title":"Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion","volume":"57","author":"Allen","year":"2016","journal-title":"Epilepsia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1038\/s41431-019-0442-1","article-title":"Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing","volume":"27","author":"Bruel","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/ana.24866","article-title":"De novo KCNA2 mutations cause hereditary spastic paraplegia","volume":"81","author":"Manole","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.ajhg.2017.09.008","article-title":"High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies","volume":"101","author":"Hamdan","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/cge.13581","article-title":"Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: Is there a major genetic factor?","volume":"96","author":"Routier","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.seizure.2017.07.018","article-title":"Novel clinical manifestations in patients with KCNA2 mutations","volume":"51","author":"Sachdev","year":"2017","journal-title":"Seizure"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.seizure.2019.01.005","article-title":"Progressive myoclonus epilepsy caused by a gain-of-function KCNA2 mutation","volume":"65","author":"Canafoglia","year":"2019","journal-title":"Seizure"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1159\/000448369","article-title":"Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies","volume":"7","author":"Moller","year":"2016","journal-title":"Mol. Syndromol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.seizure.2019.04.018","article-title":"The landscape of early infantile epileptic encephalopathy in a consanguineous population","volume":"69","author":"Nashabat","year":"2019","journal-title":"Seizure"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.neuroscience.2019.08.016","article-title":"Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy","volume":"418","author":"Costain","year":"2019","journal-title":"Neuroscience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/humu.23946","article-title":"A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders","volume":"41","author":"Ngo","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101445","DOI":"10.1016\/j.scr.2019.101445","article-title":"Establishment of a human induced pluripotent stem cell (iPSC) line (HIHDNEi002-A) from a patient with developmental and epileptic encephalopathy carrying a KCNA2 (p.Arg297Gln) mutation","volume":"37","author":"Schwarz","year":"2019","journal-title":"Stem Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.3389\/fnins.2019.01135","article-title":"Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients","volume":"13","author":"Roca","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/humu.23149","article-title":"Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes","volume":"38","author":"Parrini","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.scr.2018.08.019","article-title":"Generation of an induced pluripotent stem cell (iPSC) line from a patient with developmental and epileptic encephalopathy carrying a KCNA2 (p.Leu328Val) mutation","volume":"33","author":"Schwarz","year":"2018","journal-title":"Stem Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101543","DOI":"10.1016\/j.scr.2019.101543","article-title":"Generation of an induced pluripotent stem cell (iPSC) line (HIHDNEi003-A) from a patient with developmental and epileptic encephalopathy carrying a KCNA2 (p.Thr374Ala) mutation","volume":"40","author":"Uysal","year":"2019","journal-title":"Stem Cell Res."},{"key":"ref_34","first-page":"35","article-title":"[Genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy]","volume":"58","author":"Gong","year":"2020","journal-title":"Zhonghua Er Ke Za Zhi"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.ejpn.2016.03.011","article-title":"Severe early-onset epileptic encephalopathy due to mutations in the KCNA2 gene: Expansion of the genotypic and phenotypic spectrum","volume":"20","author":"Hundallah","year":"2016","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e12456","DOI":"10.1111\/gbb.12456","article-title":"Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies","volume":"17","author":"Zhou","year":"2018","journal-title":"Genes Brain Behav."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/cge.13441","article-title":"Genotype and phenotype analysis using an epilepsy-associated gene panel in Chinese pediatric epilepsy patients","volume":"94","author":"Miao","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s00439-017-1821-8","article-title":"The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes","volume":"136","author":"Monies","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/cge.12784","article-title":"Rett-like phenotypes: Expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease","volume":"91","author":"Allou","year":"2017","journal-title":"Clin. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lal, D., Ruppert, A.K., Trucks, H., Schulz, H., de Kovel, C.G., Kasteleijn-Nolst Trenite, D., Sonsma, A.C., Koeleman, B.P., Lindhout, D., and Weber, Y.G. (2015). Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005226"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1038\/mp.2016.109","article-title":"Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability","volume":"22","author":"Riazuddin","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gunning, A.C., Fryer, V., Fasham, J., Crosby, A.H., Ellard, S., Baple, E.L., and Wright, C.F. (2020). Assessing performance of pathogenicity predictors using clinically relevant variant datasets. J. Med. Genet, 107003.","DOI":"10.1101\/2020.02.06.937169"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7793","DOI":"10.1093\/nar\/gky678","article-title":"Performance evaluation of pathogenicity-computation methods for missense variants","volume":"46","author":"Li","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1111\/epi.12200","article-title":"Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation","volume":"54","author":"Kato","year":"2013","journal-title":"Epilepsia"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Paulhus, K., Ammerman, L., and Glasscock, E. (2020). Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082802"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1085\/jgp.20028611","article-title":"Tail end of the s6 segment: Role in permeation in shaker potassium channels","volume":"120","author":"Ding","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S0006-3495(03)74850-4","article-title":"Effect of S6 tail mutations on charge movement in Shaker potassium channels","volume":"84","author":"Ding","year":"2003","journal-title":"Biophys. J."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Doring, J.H., Saffari, A., Bast, T., Brockmann, K., Ehrhardt, L., Fazeli, W., Janzarik, W.G., Kluger, G., Muhle, H., and Moller, R.S. (2020). The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood. Biomedicines, 8.","DOI":"10.3390\/biomedicines8110456"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1111\/j.1528-1167.2007.01049.x","article-title":"SCN2A mutations and benign familial neonatal-infantile seizures: The phenotypic spectrum","volume":"48","author":"Herlenius","year":"2007","journal-title":"Epilepsia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/ana.24580","article-title":"Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation","volume":"79","author":"Gardella","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1002\/ajmg.a.38840","article-title":"De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants","volume":"176","author":"Rogers","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1085\/jgp.20028569","article-title":"Scanning the intracellular S6 activation gate in the shaker K+ channel","volume":"119","author":"Hackos","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1093\/brain\/awh301","article-title":"Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia","volume":"127","author":"Imbrici","year":"2004","journal-title":"Brain"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"108303","DOI":"10.1016\/j.celrep.2020.108303","article-title":"Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy","volume":"33","author":"Shore","year":"2020","journal-title":"Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nature02270","article-title":"A proton pore in a potassium channel voltage sensor reveals a focused electric field","volume":"427","author":"Starace","year":"2004","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/humu.20654","article-title":"Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker","volume":"29","author":"Wildeman","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","article-title":"Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies","volume":"24","author":"Dong","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/humu.22932","article-title":"dbNSFP v3.0: A One-Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice-Site SNVs","volume":"37","author":"Liu","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_65","first-page":"D682","article-title":"Ensembl 2020","volume":"48","author":"Yates","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13023-019-1020-x","article-title":"The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy","volume":"14","author":"Hebebrand","year":"2019","journal-title":"Orphanet. J. 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