{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:58:36Z","timestamp":1792807116051,"version":"4.5.0"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009712","name":"Dravet Syndrome Foundation","doi-asserted-by":"publisher","award":["272016"],"award-info":[{"award-number":["272016"]}],"id":[{"id":"10.13039\/100009712","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"BMBF","doi-asserted-by":"publisher","award":["01GM1907"],"award-info":[{"award-number":["01GM1907"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH NINDS"},{"name":"Chilean National Agency for Investigation and Development"},{"name":"FamilieSCN2A foundation 2020"},{"name":"German BMBF","award":["01GM2210B"],"award-info":[{"award-number":["01GM2210B"]}]},{"name":"FNR in Luxembourg","award":["NTER\/DFG\/21\/16394868 MechEPI2"],"award-info":[{"award-number":["NTER\/DFG\/21\/16394868 MechEPI2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making.<\/jats:p>\n                  <jats:p>We aggregated genetic and clinical data from 172 individuals with likely pathogenic\/pathogenic (lp\/p) SLC6A1 variants and functional data for 184 variants (14.1% lp\/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches.<\/jats:p>\n                  <jats:p>The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 \u00d7 10\u22123, 95% confidence interval: 1.5\u201315.3).<\/jats:p>\n                  <jats:p>In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https:\/\/slc6a1-portal.broadinstitute.org\/).<\/jats:p>","DOI":"10.1093\/brain\/awad292","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T18:06:22Z","timestamp":1693418782000},"page":"5198-5208","source":"Crossref","is-referenced-by-count":31,"title":["<i>SLC6A1<\/i>\n                    variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9937-9764","authenticated-orcid":false,"given":"Arthur","family":"Stefanski","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute and Epilepsy Center, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"P\u00e9rez-Palma","sequence":"additional","affiliation":[{"name":"Universidad del Desarrollo, Centro de Gen\u00e9tica y Gen\u00f3mica, Facultad de Medicina Cl\u00ednica Alemana , Santiago de Chile 7610658 , Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Br\u00fcnger","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Medical Faculty of the University of Cologne, University Hospital of Cologne , Cologne 50931 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Montanucci","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute and Epilepsy Center, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius","family":"Gati","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California , Los Angeles, CA 90089 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Kl\u00f6ckner","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7356-3109","authenticated-orcid":false,"given":"Katrine M","family":"Johannesen","sequence":"additional","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre , Dianalund 4293 , Denmark"},{"name":"Department of Genetics, University Hospital of Copenhagen, Rigshispitalet , Copenhagen 2100 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Goodspeed","sequence":"additional","affiliation":[{"name":"Children\u2019s Health, Medical Center , Dallas, TX 75235 , USA"},{"name":"Department of Pediatrics, University of Texas Southwestern Medical Center , Dallas, TX 75390 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4217-5277","authenticated-orcid":false,"given":"Marie","family":"Macnee","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Medical Faculty of the University of Cologne, University Hospital of Cologne , Cologne 50931 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander T","family":"Deng","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Guys and St Thomas NHS Trust , London SE19RT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel","family":"Aledo-Serrano","sequence":"additional","affiliation":[{"name":"Epilepsy Program, Neurology Department, Hospital Ruber Internacional , Madrid 28034 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem","family":"Borovikov","sequence":"additional","affiliation":[{"name":"Research and Counseling Department, Research Centre for Medical Genetics , Moscow 115478 , Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maina","family":"Kava","sequence":"additional","affiliation":[{"name":"Department of Neurology and Metabolic Medicine, Perth Children\u2019s Hospital , Perth 6009 , Australia"},{"name":"School of Paediatrics and Child Health, UWA Medical School, University of Western Australia , Perth 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan M","family":"Bouman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam 3015GD , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M J","family":"Hajianpour","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics and Genomics, Albany Medical College, Albany Med Health System , Albany, NY 12208 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deb K","family":"Pal","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College , London SE58AF , UK"},{"name":"Department of Basic and Clinical Neurosciences, King\u2019s College Hospital , London SE59RS , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5346-8497","authenticated-orcid":false,"given":"Marc","family":"Engelen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Amsterdam Public Health, Amsterdam University Medical Center , Amsterdam 1081HV , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eveline E O","family":"Hagebeuk","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Stichting Epilepsie Instellingen Nederland (SEIN) , Heemstede and Zwolle 2103SW , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Shinawi","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics, St.Louis Children\u2019s Hospital, Washington University School of Medicine , St. Louis, MO 63110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis R","family":"Heidlebaugh","sequence":"additional","affiliation":[{"name":"Autism and Developmental Medicine Institute, Geisinger , Danville, PA 17837 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Oetjens","sequence":"additional","affiliation":[{"name":"Autism and Developmental Medicine Institute, Geisinger , Danville, PA 17837 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor L","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Regional Genetics, Anaheim, Southern California Kaiser Permanente Medical Group , CA 92806 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini , Genoa 16147 , Italy"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa , Genoa 16132 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda S","family":"Freed","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine , Pasadena, CA 91101 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line","family":"Futtrup","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Regional Hospital of Central Jutland , Viborg 8800 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Balslev","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Regional Hospital of Central Jutland , Viborg 8800 , Denmark"},{"name":"Centre for Educational Development, Aarhus University , Aarhus 8200 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Abul\u00ed","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics and Medicine Genetics Group, VHIR, University Hospital Vall d\u2019Hebron , Barcelona 08035 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Danvoye","sequence":"additional","affiliation":[{"name":"Department of Neurology, Universit\u00e9 catholique de Louvain, Cliniques universitaires Saint-Luc , Brussels 1200 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Lederer","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, Institute for Pathology and Genetics , Gosselies 6041 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tugce","family":"Balci","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, Western University , London, ON N6A3K7 , Canada"},{"name":"Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute , London, ON N6A5A5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam Nabavi","family":"Nouri","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Division of Pediatric Neurology, London Health Sciences Centre , London, ON N6A5W9 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Butler","sequence":"additional","affiliation":[{"name":"GeneDx , Gaithersburg, MD 20877 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Drewes","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, UPMC Children\u2019s Hospital of Pittsburgh , Pittsburgh, PA 15224 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalene","family":"van Engelen","sequence":"additional","affiliation":[{"name":"Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre , London, ON N6A5W9 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine B","family":"Howell","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Children\u2019s Hospital , Melbourne, VIC 3052 , Australia"},{"name":"Department of Pediatrics, University of Melbourne , Melbourne, VIC 3052 , Australia"},{"name":"Murdoch Children\u2019s Research Institute , Melbourne, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Khoury","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute and Epilepsy Center, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8698-3770","authenticated-orcid":false,"given":"Patrick","family":"May","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine, University of Luxembourg , Esch-sur-Alzette 4362 , Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marena","family":"Trinidad","sequence":"additional","affiliation":[{"name":"Translational Genomics, BioMarin Pharmaceutical Inc. , Novato, CA 94949 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Froelich","sequence":"additional","affiliation":[{"name":"Translational Genomics, BioMarin Pharmaceutical Inc. , Novato, CA 94949 , USA"}],"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 , Leipzig 04103 , Germany"},{"name":"Center for Rare Diseases, University of Leipzig Medical Center , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Tiller","sequence":"additional","affiliation":[{"name":"SLC6A1 Connect , Frisco, TX 75034 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber N","family":"Freed","sequence":"additional","affiliation":[{"name":"SLC6A1 Connect , Frisco, TX 75034 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-5436","authenticated-orcid":false,"given":"Jing-Qiong","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center , Nashville, TN 37240 , USA"},{"name":"Neuroscience Graduate Program, Vanderbilt University , Nashville, TN 37235 , USA"},{"name":"Department of Neurology, Vanderbilt Brain Institute , Nashville, TN 37235 , USA"},{"name":"Department of Pharmacology, Vanderbilt University , Nashville, TN 37232 , USA"},{"name":"Vanderbilt Kennedy Center of Human Development , Nashville, TN 37203 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Wuster","sequence":"additional","affiliation":[{"name":"Translational Genomics, BioMarin Pharmaceutical Inc. , Novato, CA 94949 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikke S","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre , Dianalund 4293 , Denmark"},{"name":"Department of Regional Health Research, University of Southern Denmark , Odense 5000 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Lal","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute and Epilepsy Center, Cleveland Clinic , Cleveland, OH 44195 , USA"},{"name":"Stanley Center of Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, MA 02142 , USA"},{"name":"Department of Neurology, University of Texas Health Sciences Center at Houston , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,30]]},"reference":[{"key":"2023120106134647200_awad292-B1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3389\/fncel.2014.00161","article-title":"Structure, function, and plasticity of GABA transporters","volume":"8","author":"Scimemi","year":"2014","journal-title":"Front Cell Neurosci"},{"key":"2023120106134647200_awad292-B2","doi-asserted-by":"crossref","first-page":"fcaa170","DOI":"10.1093\/braincomms\/fcaa170","article-title":"Current knowledge of SLC6A1-related neurodevelopmental disorders","volume":"2","author":"Goodspeed","year":"2020","journal-title":"Brain Commun"},{"key":"2023120106134647200_awad292-B3","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/epi.13986","article-title":"Defining the phenotypic spectrum of SLC6A1 mutations","volume":"59","author":"Johannesen","year":"2018","journal-title":"Epilepsia"},{"key":"2023120106134647200_awad292-B4","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.ajhg.2015.02.016","article-title":"Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures","volume":"96","author":"Carvill","year":"2015","journal-title":"Am J Hum Genet"},{"key":"2023120106134647200_awad292-B5","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1093\/brain\/awab207","article-title":"Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons","volume":"144","author":"Mermer","year":"2021","journal-title":"Brain"},{"key":"2023120106134647200_awad292-B6","doi-asserted-by":"crossref","first-page":"e135","DOI":"10.1111\/epi.14531","article-title":"SLC6A1 Variants identified in epilepsy patients reduce \u03b3-aminobutyric acid transport","volume":"59","author":"Mattison","year":"2018","journal-title":"Epilepsia"},{"key":"2023120106134647200_awad292-B7","doi-asserted-by":"crossref","first-page":"112973","DOI":"10.1016\/j.expneurol.2019.112973","article-title":"A missense mutation in SLC6A1 associated with lennox-gastaut syndrome impairs GABA transporter 1 protein trafficking and function","volume":"320","author":"Cai","year":"2019","journal-title":"Exp Neurol"},{"key":"2023120106134647200_awad292-B8","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13041-020-00612-6","article-title":"Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism","volume":"13","author":"Wang","year":"2020","journal-title":"Mol Brain"},{"key":"2023120106134647200_awad292-B9","doi-asserted-by":"crossref","first-page":"113723","DOI":"10.1016\/j.expneurol.2021.113723","article-title":"Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD","volume":"342","author":"Poliquin","year":"2021","journal-title":"Exp Neurol"},{"key":"2023120106134647200_awad292-B10","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1136\/jmedgenet-2021-107694","article-title":"Neurodevelopmental phenotypes associated with pathogenic variants in SLC6A1","volume":"59","author":"Kahen","year":"2022","journal-title":"J Med Genet"},{"key":"2023120106134647200_awad292-B11","article-title":"High-throughput discovery of SLC6A1 variants affecting GABA transport in neurological disorders","volume-title":"medRxiv","author":"Silva"},{"key":"2023120106134647200_awad292-B12","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.tins.2020.05.004","article-title":"Neurodevelopmental disorders: From genetics to functional pathways","volume":"43","author":"Parenti","year":"2020","journal-title":"Trends Neurosci"},{"key":"2023120106134647200_awad292-B13","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/nrg2707","article-title":"Kinase mutations in human disease: Interpreting genotype-phenotype relationships","volume":"11","author":"Lahiry","year":"2010","journal-title":"Nat Rev Genet"},{"key":"2023120106134647200_awad292-B14","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s11689-010-9055-2","article-title":"The genetic basis of non-syndromic intellectual disability: A review","volume":"2","author":"Kaufman","year":"2010","journal-title":"J Neurodev Disord"},{"issue":"Pt B","key":"2023120106134647200_awad292-B15","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.pnpbp.2017.09.014","article-title":"Glutamatergic synapses in neurodevelopmental disorders","volume":"84","author":"Moretto","year":"2018","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"2023120106134647200_awad292-B16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41436-019-0612-0","article-title":"The CHD4-related syndrome: A comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis","volume":"22","author":"Weiss","year":"2020","journal-title":"Genet Med"},{"key":"2023120106134647200_awad292-B17","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1007\/s00018-006-6061-3","article-title":"The neuroligin and neurexin families: From structure to function at the synapse","volume":"63","author":"Lis\u00e9","year":"2006","journal-title":"Cell Mol Life Sci"},{"key":"2023120106134647200_awad292-B18","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1136\/jmedgenet-2016-104509","article-title":"GRIN2B Encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects","volume":"54","author":"Platzer","year":"2017","journal-title":"J Med Genet"},{"key":"2023120106134647200_awad292-B19","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.hrthm.2009.09.069","article-title":"An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for brugada syndrome genetic testing","volume":"7","author":"Kapplinger","year":"2010","journal-title":"Heart Rhythm"},{"key":"2023120106134647200_awad292-B20","doi-asserted-by":"crossref","first-page":"eaay6848","DOI":"10.1126\/scitranslmed.aay6848","article-title":"Predicting functional effects of missense variants in voltage-gated sodium and calcium channels","volume":"12","author":"Heyne","year":"2020","journal-title":"Sci Transl Med"},{"key":"2023120106134647200_awad292-B21","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1093\/brain\/awy304","article-title":"GRIN2A-related Disorders: Genotype and functional consequence predict phenotype","volume":"142","author":"Strehlow","year":"2019","journal-title":"Brain"},{"key":"2023120106134647200_awad292-B22","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2100066118","article-title":"Comparative structural analysis of human nav1.1 and nav1.5 reveals mutational hotspots for sodium channelopathies","volume":"118","author":"Pan","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023120106134647200_awad292-B23","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1038\/s41586-022-04814-x","article-title":"Structural basis of GABA reuptake inhibition","volume":"606","author":"Motiwala","year":"2022","journal-title":"Nature"},{"key":"2023120106134647200_awad292-B24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.pediatrneurol.2019.02.015","article-title":"Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: Clinical review","volume":"97","author":"Olson","year":"2019","journal-title":"Pediatr Neurol"},{"key":"2023120106134647200_awad292-B25","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.ajhg.2019.07.010","article-title":"Rare De Novo missense variants in RNA helicase DDX6 cause intellectual disability and dysmorphic features and lead to P-body defects and RNA dysregulation","volume":"105","author":"Balak","year":"2019","journal-title":"Am J Hum Genet"},{"key":"2023120106134647200_awad292-B26","doi-asserted-by":"crossref","first-page":"637890","DOI":"10.3389\/fneur.2021.637890","article-title":"ATP1A3-Related Disorders: An ever-expanding clinical Spectrum","volume":"12","author":"Salles","year":"2021","journal-title":"Front Neurol"},{"key":"2023120106134647200_awad292-B27","doi-asserted-by":"crossref","first-page":"e2046","DOI":"10.1212\/WNL.0000000000200660","article-title":"Spectrum of phenotypic, genetic, and functional characteristics in patients with epilepsy with KCNC2 pathogenic variants","volume":"98","author":"Schwarz","year":"2022","journal-title":"Neurology"},{"key":"2023120106134647200_awad292-B28","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/brain\/awac305","article-title":"Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes","volume":"146","author":"Br\u00fcnger","year":"2022","journal-title":"Brain"},{"key":"2023120106134647200_awad292-B29","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.ajhg.2017.08.004","article-title":"Spatial clustering of de Novo missense mutations identifies candidate neurodevelopmental disorder-associated genes","volume":"101","author":"Lelieveld","year":"2017","journal-title":"Am J Hum Genet"},{"key":"2023120106134647200_awad292-B30","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.gim.2021.11.004","article-title":"Structural mapping of GABRB3 variants reveals genotype-phenotype correlations","volume":"24","author":"Johannesen","year":"2022","journal-title":"Genet Med"},{"issue":"D1","key":"2023120106134647200_awad292-B31","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"Clinvar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2023120106134647200_awad292-B32","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2019.05.020","article-title":"Ultra-Rare genetic variation in the epilepsies: A whole-exome sequencing study of 17,606 individuals","volume":"105","author":"Epi25 Collaborative","year":"2019","journal-title":"Am J Hum Genet"},{"key":"2023120106134647200_awad292-B33","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"2023120106134647200_awad292-B34","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"2023120106134647200_awad292-B35","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/gim.2017.26","article-title":"Using high-resolution variant frequencies to empower clinical genome interpretation","volume":"19","author":"Whiffin","year":"2017","journal-title":"Genet Med"},{"key":"2023120106134647200_awad292-B36","author":"Schr\u00f6dinger"},{"key":"2023120106134647200_awad292-B37","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1093\/bioinformatics\/btl461","article-title":"Bio3d: An R package for the comparative analysis of protein structures","volume":"22","author":"Grant","year":"2006","journal-title":"Bioinforma Oxf Engl"},{"key":"2023120106134647200_awad292-B38","author":"Tenny"},{"key":"2023120106134647200_awad292-B39","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1093\/brain\/awaa051","article-title":"A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants","volume":"143","author":"L\u00f3pez-Rivera","year":"2020","journal-title":"Brain"},{"key":"2023120106134647200_awad292-B40","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/brain\/awac042","article-title":"Cause-specific mortality and life years lost in people with epilepsy: A danish cohort study","volume":"146","author":"Dreier","year":"2023","journal-title":"Brain"},{"key":"2023120106134647200_awad292-B41","doi-asserted-by":"crossref","first-page":"160018","DOI":"10.1038\/sdata.2016.18","article-title":"The FAIR guiding principles for scientific data management and stewardship","volume":"3","author":"Wilkinson","year":"2016","journal-title":"Sci Data"},{"key":"2023120106134647200_awad292-B42","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1016\/j.bpj.2008.11.070","article-title":"Ezrin mediates tethering of the \u03b3-aminobutyric acid transporter GAT1 to actin filaments via a C-terminal PDZ-interacting domain","volume":"96","author":"Imoukhuede","year":"2009","journal-title":"Biophys J"},{"key":"2023120106134647200_awad292-B43","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1021\/bi00613a026","article-title":"Conformational preferences of amino acids in globular proteins","volume":"17","author":"Levitt","year":"1978","journal-title":"Biochemistry"},{"key":"2023120106134647200_awad292-B44","first-page":"45","article-title":"Prediction of the secondary structure of proteins from their amino acid sequence","volume":"47","author":"Chou","year":"1978","journal-title":"Adv Enzymol Relat Areas Mol Biol"},{"key":"2023120106134647200_awad292-B45","doi-asserted-by":"crossref","first-page":"165a","DOI":"10.1016\/j.bpj.2021.11.1909","article-title":"Genomic analysis of AlphaFold2-predicted structures identifies maps of 3D essential sites in 243 neurodevelopmental disorder-associated proteins","volume":"121","author":"Iqbal","year":"2022","journal-title":"Biophys J"},{"key":"2023120106134647200_awad292-B46","doi-asserted-by":"crossref","first-page":"28201","DOI":"10.1073\/pnas.2002660117","article-title":"Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants","volume":"117","author":"Iqbal","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023120106134647200_awad292-B47","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/pro.3746","article-title":"Varsite: Disease variants and protein structure","volume":"29","author":"Laskowski","year":"2020","journal-title":"Protein Sci"},{"key":"2023120106134647200_awad292-B48","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13073-017-0509-y","article-title":"Mapping genetic variations to three-dimensional protein structures to enhance variant interpretation: A proposed framework","volume":"9","author":"Glusman","year":"2017","journal-title":"Genome Med"},{"key":"2023120106134647200_awad292-B49","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1093\/brain\/awu022","article-title":"Dopamine transporter deficiency syndrome: Phenotypic spectrum from infancy to adulthood","volume":"137","author":"Ng","year":"2014","journal-title":"Brain"},{"key":"2023120106134647200_awad292-B50","doi-asserted-by":"crossref","first-page":"11270","DOI":"10.1074\/jbc.M109.093658","article-title":"Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine","volume":"285","author":"Field","year":"2010","journal-title":"J Biol Chem"},{"issue":"1\u20132","key":"2023120106134647200_awad292-B51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/09687688.2018.1448123","article-title":"Structural biology of solute carrier (SLC) membrane transport proteins","volume":"34","author":"Bai","year":"2017","journal-title":"Mol Membr Biol"},{"key":"2023120106134647200_awad292-B52","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1126\/science.1166777","article-title":"A competitive inhibitor traps LeuT in an open-to-out conformation","volume":"322","author":"Singh","year":"2008","journal-title":"Science"},{"key":"2023120106134647200_awad292-B53","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nature03978","article-title":"Crystal structure of a bacterial homologue of na+\/cl\u2013dependent neurotransmitter transporters","volume":"437","author":"Yamashita","year":"2005","journal-title":"Nature"},{"key":"2023120106134647200_awad292-B54","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.sbi.2019.03.011","article-title":"Insights into the mechanism and pharmacology of neurotransmitter sodium symporters","volume":"54","author":"Navratna","year":"2019","journal-title":"Curr Opin Struct Biol"},{"key":"2023120106134647200_awad292-B55","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41586-019-1135-1","article-title":"Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport","volume":"569","author":"Coleman","year":"2019","journal-title":"Nature"},{"issue":"2\u20133","key":"2023120106134647200_awad292-B56","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.mam.2012.07.002","article-title":"SLC6 Transporters: Structure, function, regulation, disease association and therapeutics","volume":"34","author":"Pramod","year":"2013","journal-title":"Mol Aspects Med"},{"key":"2023120106134647200_awad292-B57","doi-asserted-by":"crossref","first-page":"4470","DOI":"10.1523\/JNEUROSCI.23-11-04470.2003","article-title":"A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters","volume":"23","author":"Hahn","year":"2003","journal-title":"J Neurosci"},{"key":"2023120106134647200_awad292-B58","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1038\/s41380-021-01341-5","article-title":"The dopamine transporter gene SLC6A3: Multidisease risks","volume":"27","author":"Reith","year":"2022","journal-title":"Mol Psychiatry"},{"key":"2023120106134647200_awad292-B59","doi-asserted-by":"crossref","first-page":"e464","DOI":"10.1038\/tp.2014.90","article-title":"SLC6A3 Coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking","volume":"4","author":"Bowton","year":"2014","journal-title":"Transl Psychiatry"},{"key":"2023120106134647200_awad292-B60","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1093\/eurheartj\/ehy412","article-title":"SCN5A Mutations in 442 neonates and children: Genotype-phenotype correlation and identification of higher-risk subgroups","volume":"39","author":"Baruteau","year":"2018","journal-title":"Eur Heart J"},{"key":"2023120106134647200_awad292-B61","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1212\/WNL.0b013e31820c309b","article-title":"Genotype-phenotype associations in SCN1A-related epilepsies","volume":"76","author":"Zuberi","year":"2011","journal-title":"Neurology"},{"key":"2023120106134647200_awad292-B62","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s13073-021-00900-3","article-title":"Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders","volume":"13","author":"Mannucci","year":"2021","journal-title":"Genome Med"},{"key":"2023120106134647200_awad292-B63","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1007\/s00415-018-9033-2","article-title":"Correlation of phenotype with genotype and protein structure in RYR1-related disorders","volume":"265","author":"Todd","year":"2018","journal-title":"J Neurol"},{"key":"2023120106134647200_awad292-B64","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/s41436-020-0752-2","article-title":"Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1","volume":"22","author":"Ottenhoff","year":"2020","journal-title":"Genet Med"},{"key":"2023120106134647200_awad292-B65","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.ajhg.2017.04.003","article-title":"International cooperation to enable the diagnosis of all rare genetic diseases","volume":"100","author":"Boycott","year":"2017","journal-title":"Am J Hum Genet"},{"key":"2023120106134647200_awad292-B66","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/ng.3304","article-title":"Factors influencing success of clinical genome sequencing across a broad spectrum of disorders","volume":"47","author":"Taylor","year":"2015","journal-title":"Nat Genet"},{"key":"2023120106134647200_awad292-B67","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1056\/NEJMoa1714458","article-title":"Effect of genetic diagnosis on patients with previously undiagnosed disease","volume":"379","author":"Splinter","year":"2018","journal-title":"N Engl J Med"},{"key":"2023120106134647200_awad292-B68","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s11689-022-09449-7","article-title":"Consistency of parent-report SLC6A1 data in simons searchlight with provider-based publications","volume":"14","author":"Bain","year":"2022","journal-title":"J Neurodev Disord"},{"key":"2023120106134647200_awad292-B69","doi-asserted-by":"crossref","first-page":"e1163","DOI":"10.1212\/WNL.0000000000200028","article-title":"Development and validation of a prediction model for early diagnosis of SCN1A-related epilepsies","volume":"98","author":"Brunklaus","year":"2022","journal-title":"Neurology"},{"key":"2023120106134647200_awad292-B70","doi-asserted-by":"crossref","first-page":"104115","DOI":"10.1016\/j.ebiom.2022.104115","article-title":"Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning","volume":"81","author":"Bo\u00dfelmann","year":"2022","journal-title":"EBioMedicine"},{"key":"2023120106134647200_awad292-B71","doi-asserted-by":"crossref","first-page":"3473","DOI":"10.1093\/brain\/awz292","article-title":"Polygenic burden in focal and generalized epilepsies","volume":"142","author":"Leu","year":"2019","journal-title":"Brain"},{"key":"2023120106134647200_awad292-B72","doi-asserted-by":"crossref","first-page":"104098","DOI":"10.1016\/j.ebiom.2022.104098","article-title":"The role of common genetic variation in presumed monogenic epilepsies","volume":"81","author":"Campbell","year":"2022","journal-title":"EBioMedicine"},{"key":"2023120106134647200_awad292-B73","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.biopsych.2018.12.015","article-title":"Predicting polygenic risk of psychiatric disorders","volume":"86","author":"Martin","year":"2019","journal-title":"Biol Psychiatry"},{"key":"2023120106134647200_awad292-B74","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41586-018-0566-4","article-title":"Common genetic variants contribute to risk of rare severe neurodevelopmental disorders","volume":"562","author":"Niemi","year":"2018","journal-title":"Nature"},{"key":"2023120106134647200_awad292-B75","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/toxsci\/kfab022","article-title":"The impact of environmental factors on monogenic Mendelian diseases","volume":"181","author":"Tukker","year":"2021","journal-title":"Toxicol Sci"},{"key":"2023120106134647200_awad292-B76","doi-asserted-by":"crossref","first-page":"3635","DOI":"10.1038\/s41467-020-17374-3","article-title":"Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions","volume":"11","author":"Fahed","year":"2020","journal-title":"Nat Commun"},{"key":"2023120106134647200_awad292-B77","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1038\/s41591-020-1103-1","article-title":"Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome","volume":"26","author":"Davies","year":"2020","journal-title":"Nat Med"},{"key":"2023120106134647200_awad292-B78","doi-asserted-by":"crossref","first-page":"4496","DOI":"10.1038\/s41380-020-0654-3","article-title":"Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion","volume":"26","author":"Cleynen","year":"2021","journal-title":"Mol Psychiatry"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awad292\/53478638\/awad292.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/12\/5198\/53962835\/awad292.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/12\/5198\/53962835\/awad292.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T01:15:45Z","timestamp":1701393345000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/146\/12\/5198\/7255896"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,30]]},"references-count":78,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,8,30]]},"published-print":{"date-parts":[[2023,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awad292","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,12]]},"published":{"date-parts":[[2023,8,30]]}}}