{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:50:26Z","timestamp":1788544226708,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT093205MA;WT104033AIA;212285\/Z\/18\/Z"],"award-info":[{"award-number":["WT093205MA;WT104033AIA;212285\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in <jats:italic>Xenopus<\/jats:italic> oocytes and their functional properties assessed using two\u2010electrode voltage clamp.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified novel de novo variants in <jats:italic>KCNA6<\/jats:italic> in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore\u2010lining S6 \u03b1\u2010helix of K<jats:sub>V<\/jats:sub>1.6. A prominent finding of functional characterization in <jats:italic>Xenopus<\/jats:italic> oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co\u2010expressed with wild\u2010type K<jats:sub>V<\/jats:sub>1.6 or K<jats:sub>V<\/jats:sub>1.1 subunits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This is the first report of de novo nonsynonymous variants in <jats:italic>KCNA6<\/jats:italic> associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain\u2010of\u2010function feature is likely to underlie the neurological phenotype in our patients. Our data highlight <jats:italic>KCNA6<\/jats:italic> as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17455","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T14:55:52Z","timestamp":1667314552000},"page":"443-455","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["De novo <i>KCNA6<\/i> variants with attenuated <scp>K<sub>V<\/sub><\/scp>1.6 channel deactivation in patients with epilepsy"],"prefix":"10.1111","volume":"64","author":[{"given":"Vincenzo","family":"Salpietro","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"},{"name":"Department of Biotechnological and Applied Clinical Sciences (DISCAB) University of L'Aquila  L'Aquila Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7123-8011","authenticated-orcid":false,"given":"Valentina","family":"Galassi Deforie","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-9877","authenticated-orcid":false,"given":"Stephanie","family":"Efthymiou","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emer","family":"O'Connor","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Marc\u00e9\u2010Grau","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, University Hospital Vall d'Hebron Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-1476","authenticated-orcid":false,"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI) University of Genoa  16124 Genoa Italy"},{"name":"Unit of Pediatric Neurology IRCCS, Istituto \u201cGiannina Gaslini\u201d  Genoa 16123 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Zara","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI) University of Genoa  16124 Genoa Italy"},{"name":"Medical Genetics Unit IRCCS, Istituto \u201cGiannina Gaslini\u201d  Genoa 16123 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9475-0934","authenticated-orcid":false,"given":"Michelle M.","family":"Morrow","sequence":"additional","affiliation":[{"name":"GeneDx  Maryland Gaithersburg USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"SYNAPS Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Reich","sequence":"additional","affiliation":[{"name":"GeneDx  Maryland Gaithersburg USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Blevins","sequence":"additional","affiliation":[{"name":"GeneDx  Maryland Gaithersburg USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"Sala\u2010Coromina","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, University Hospital Vall d'Hebron Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-6721","authenticated-orcid":false,"given":"Andrea","family":"Accogli","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI) University of Genoa  16124 Genoa Italy"},{"name":"Medical Genetics Unit IRCCS, Istituto \u201cGiannina Gaslini\u201d  Genoa 16123 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Fortuna","sequence":"additional","affiliation":[{"name":"Istituto Italiano di Tecnologia (IIT)  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Alesandrini","sequence":"additional","affiliation":[{"name":"Neuropediatrics Unit Centre Hospitalier Universitaire Nantes  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9533-7217","authenticated-orcid":false,"given":"P. Y. Billie","family":"Au","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine University of Calgary  Alberta Calgary Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilika Shah","family":"Singhal","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pediatrics, UCSF Benioff Children's Hospital University of California  California San Francisco USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Cogne","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire Nantes Service de G\u00e9n\u00e9tique M\u00e9dicale  Nantes France"},{"name":"Universit\u00e9 de Nantes, CNRS, INSERM L'Institut du Thorax  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Isidor","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire Nantes Service de G\u00e9n\u00e9tique M\u00e9dicale  Nantes France"},{"name":"Universit\u00e9 de Nantes, CNRS, INSERM L'Institut du Thorax  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"},{"name":"Queen Square Centre for Neuromuscular Diseases National Hospital for Neurology and Neurosurgery  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfons","family":"Macaya","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, University Hospital Vall d'Hebron Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6696-3545","authenticated-orcid":false,"given":"Dimitri M.","family":"Kullmann","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy UCL Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8727-9184","authenticated-orcid":false,"given":"Roope","family":"M\u00e4nnikk\u00f6","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease UCL Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12763"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61455-X"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-017-8914-1_25"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcl.2015.03.013"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.251"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12954"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2016.11.030"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(99)00535-9"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00978"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/369289a0"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awf130"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncpneuro0178"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/345535a0"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2020.01.013"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2019.12.002"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1094-136"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/122.5.817"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200010)48:4<647::AID-ANA12>3.0.CO;2-Q"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3239"},{"issue":"1","key":"e_1_2_11_21_1","first-page":"37","article-title":"Genetic neurological channelopathies: molecular genetics and clinical phenotypes","volume":"87","author":"Spillane J","year":"2016","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003309"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-016-0486-0"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1990.tb08299.x"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.018333"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.07.002"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021409"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/34916"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1080\/09687680310001597749"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13709"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1352\/1944-7558-126.6.439"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22844"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky427"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr703"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/elps.1150181505"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-0583-2"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27286"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24905"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106373"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00034"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx184"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu056"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25522"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2016.00121"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.17455","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/epi.17455","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.17455","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T23:35:21Z","timestamp":1692574521000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.17455"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,5]]},"references-count":43,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1111\/epi.17455"],"URL":"https:\/\/doi.org\/10.1111\/epi.17455","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,5]]},"assertion":[{"value":"2022-06-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}