{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:31:24Z","timestamp":1791876684998,"version":"4.3.4"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004040","name":"KU Leuven","doi-asserted-by":"publisher","award":["C1\u2014C14-17-107"],"award-info":[{"award-number":["C1\u2014C14-17-107"]}],"id":[{"id":"10.13039\/501100004040","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FWO-Vlaanderen","award":["G0B2819N"],"award-info":[{"award-number":["G0B2819N"]}]},{"DOI":"10.13039\/501100003132","name":"IWT","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003132","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Belgian National Lottery"},{"name":"ALS Liga Belgi\u00eb"},{"DOI":"10.13039\/501100003130","name":"Research Foundation\u2014Flanders","doi-asserted-by":"publisher","award":["1164018N"],"award-info":[{"award-number":["1164018N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010648","name":"university hospitals of Leuven, Belgium","doi-asserted-by":"publisher","award":["S61184"],"award-info":[{"award-number":["S61184"]}],"id":[{"id":"10.13039\/501100010648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"European Union\u2019s Horizon 2020 research and innovation programme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health\u223cHolland"},{"DOI":"10.13039\/100016036","name":"Top Sector Life Sciences & Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016036","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002561","name":"ALS Foundation Netherlands","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002561","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking.<\/jats:p>\n               <jats:p>We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE.<\/jats:p>\n               <jats:p>We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool.<\/jats:p>\n               <jats:p>We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 \u00d7 10\u22125). Isolated risk factors in ATXN1, ATXN2, NIPA1 and\/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%.<\/jats:p>\n               <jats:p>This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.<\/jats:p>","DOI":"10.1093\/brain\/awad120","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T17:26:02Z","timestamp":1681320362000},"page":"3760-3769","source":"Crossref","is-referenced-by-count":87,"title":["Genetic variability in sporadic amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3005-3619","authenticated-orcid":false,"given":"Sien Hilde","family":"Van Daele","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Experimental Neurology, KU Leuven\u2014University of Leuven, and Leuven Institute for Neuroscience and Disease (LIND) , 3000 Leuven , Belgium"},{"name":"VIB, Center for Brain & Disease Research, Laboratory of Neurobiology , 3000 Leuven , Belgium"},{"name":"Department of Neurology, University Hospitals Leuven , 3000 Leuven , Belgium"},{"name":"Department of Human genetics, University Hospitals Leuven , 3000 Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Moisse","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Experimental Neurology, KU Leuven\u2014University of Leuven, and Leuven Institute for Neuroscience and Disease (LIND) , 3000 Leuven , Belgium"},{"name":"VIB, Center for Brain & Disease Research, Laboratory of Neurobiology , 3000 Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4161-4004","authenticated-orcid":false,"given":"Joke J F A","family":"van Vugt","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona A J","family":"Zwamborn","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"van der Spek","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"van Rheenen","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristel","family":"Van Eijk","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Kenna","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Corcia","sequence":"additional","affiliation":[{"name":"Centre SLA, CHRU de Tours , 37044 Tours , France"},{"name":"UMR 1253, iBrain, Universit\u00e9 de Tours, Inserm , 37032 Tours , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Vourc'h","sequence":"additional","affiliation":[{"name":"UMR 1253, iBrain, Universit\u00e9 de Tours, Inserm , 37032 Tours , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Couratier","sequence":"additional","affiliation":[{"name":"Centre SLA, CHU Limoges , 87042 Limoges , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orla","family":"Hardiman","sequence":"additional","affiliation":[{"name":"Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute , Dublin D02 PN40 , Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3915-2135","authenticated-orcid":false,"given":"Russell","family":"McLaughin","sequence":"additional","affiliation":[{"name":"Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin , Dublin D02 PN40 , Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Gotkine","sequence":"additional","affiliation":[{"name":"The Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem , 91120 Jerusalem , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Drory","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tel-Aviv Sourasky Medical Centre , 64239 Tel Aviv , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5963-7426","authenticated-orcid":false,"given":"Nicola","family":"Ticozzi","sequence":"additional","affiliation":[{"name":"Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano , 20149 Milano , Italy"},{"name":"Department of Pathophysiology and Transplantation, \u2018Dino Ferrari\u2019 Center, Universit\u00e0 degli Studi di Milano , 20122 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-3854","authenticated-orcid":false,"given":"Vincenzo","family":"Silani","sequence":"additional","affiliation":[{"name":"Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano , 20149 Milano , Italy"},{"name":"Department of Pathophysiology and Transplantation, \u2018Dino Ferrari\u2019 Center, Universit\u00e0 degli Studi di Milano , 20122 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Ratti","sequence":"additional","affiliation":[{"name":"Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano , 20149 Milano , Italy"},{"name":"Department of Medical Biotechnology and Translational Medicine, Universit\u00e0 degli Studi di Milano , 20133 Milano , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamede","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Instituto de Fisiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisbon , Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas S","family":"Mora Pardina","sequence":"additional","affiliation":[{"name":"ALS Unit, Hospital University San Rafael , 28016 Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Povedano","sequence":"additional","affiliation":[{"name":"Servei de Neurologia, HUB-IDIBELL , 08908 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Neurosciences, Ume\u00e5 University , 901 87 Ume\u00e5 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Weber","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit\/ALS Clinic, Kantonsspital St. Gallen , 9007 St. Gallen , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazli A","family":"Ba\u015fak","sequence":"additional","affiliation":[{"name":"Ko\u00e7 University, School of Medicine, KUTTAM-NDAL , 34010 Istanbul , Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Shaw","sequence":"additional","affiliation":[{"name":"Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience , London SE5 9RT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8925-2567","authenticated-orcid":false,"given":"Pamela J","family":"Shaw","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield , Sheffield S10 2HQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen E","family":"Morrison","sequence":"additional","affiliation":[{"name":"School of Medicine, Dentistry and Biomedical Sciences, Queen\u2019s University Belfast , Belfast BT9 7BL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E","family":"Landers","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Massachusetts Medical School , Worcester, MA 01655 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D","family":"Glass","sequence":"additional","affiliation":[{"name":"Department Neurology, Emory University School of Medicine , Atlanta, GA 30322 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7709-5883","authenticated-orcid":false,"given":"Michael A","family":"van Es","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard H","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4924-7712","authenticated-orcid":false,"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[{"name":"Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience , London SE5 9RT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Veldink","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, Utrecht University , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4010-2357","authenticated-orcid":false,"given":"Philip","family":"Van Damme","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Experimental Neurology, KU Leuven\u2014University of Leuven, and Leuven Institute for Neuroscience and Disease (LIND) , 3000 Leuven , Belgium"},{"name":"VIB, Center for Brain & Disease Research, Laboratory of Neurobiology , 3000 Leuven , Belgium"},{"name":"Department of Neurology, University Hospitals Leuven , 3000 Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,12]]},"reference":[{"key":"2023090117345677000_awad120-B1","doi-asserted-by":"crossref","first-page":"17085","DOI":"10.1038\/nrdp.2017.85","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"2023090117345677000_awad120-B2","first-page":"252","article-title":"Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis","volume":"30","author":"Volk","year":"2018","journal-title":"Med Genet."},{"key":"2023090117345677000_awad120-B3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/nn.3584","article-title":"State of play in amyotrophic lateral 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