Publication:
Genetic variability in sporadic amyotrophic lateral sclerosis

dc.contributor.coauthorVan Daele, Sien Hilde
dc.contributor.coauthorMoisse, Matthieu
dc.contributor.coauthorvan Vugt, Joke J. F. A.
dc.contributor.coauthorZwamborn, Ramona A. J.
dc.contributor.coauthorvan der Spek, Rick
dc.contributor.coauthorvan Rheenen, Wouter
dc.contributor.coauthorVan Eijk, Kristel
dc.contributor.coauthorKenna, Kevin
dc.contributor.coauthorCorcia, Philippe
dc.contributor.coauthorVourc'h, Patrick
dc.contributor.coauthorCouratier, Philippe
dc.contributor.coauthorHardiman, Orla
dc.contributor.coauthorMcLaughin, Russell
dc.contributor.coauthorGotkine, Marc
dc.contributor.coauthorDrory, Vivian
dc.contributor.coauthorTicozzi, Nicola
dc.contributor.coauthorSilani, Vincenzo
dc.contributor.coauthorRatti, Antonia
dc.contributor.coauthorde Carvalho, Mamede
dc.contributor.coauthorMora Pardina, Jesus S.
dc.contributor.coauthorPovedano, Monica
dc.contributor.coauthorAndersen, Peter M.
dc.contributor.coauthorWeber, Markus
dc.contributor.coauthorShaw, Chris
dc.contributor.coauthorShaw, Pamela J.
dc.contributor.coauthorMorrison, Karen E.
dc.contributor.coauthorLanders, John E.
dc.contributor.coauthorGlass, Jonathan D.
dc.contributor.coauthorvan Es, Michael A.
dc.contributor.coauthorvan den Berg, Leonard H.
dc.contributor.coauthorAl-Chalabi, Ammar
dc.contributor.coauthorVeldink, Jan
dc.contributor.coauthorVan Damme, Philip
dc.contributor.departmentKUTTAM (Koç University Research Center for Translational Medicine)
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorBaşak, Ayşe Nazlı
dc.contributor.schoolcollegeinstituteResearch Center
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2025-01-19T10:29:01Z
dc.date.issued2023
dc.description.abstractWith 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. 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. 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. 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 x 10(-5)). 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%. 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.
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue9
dc.description.openaccesshybrid, Green Published
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipThis work was supported by grants from the KU Leuven (C1-C14-17-107), FWO-Vlaanderen (G0B2819N), the IWT (Project MinE), the Belgian National Lottery and the ALS Liga Belgie. S.H.V.D. is funded by a PhD fellowship of the Research Foundation-Flanders (FWO) (1164018N, file number 40900). Research is furthermore funded by the Fund for Clinical Academic studies of the university hospitals of Leuven, Belgium (S61184). This project has received funding<STRONG> </STRONG>from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation pro-gramme (grant agreement no 772376-EScORIAL). The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was supported by the ALS Foundation Netherlands.
dc.description.volume146
dc.identifier.doi10.1093/brain/awad120
dc.identifier.eissn1460-2156
dc.identifier.issn0006-8950
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85169624664
dc.identifier.urihttps://doi.org/10.1093/brain/awad120
dc.identifier.urihttps://hdl.handle.net/20.500.14288/25811
dc.identifier.wos1003920000001
dc.keywordsComplex genetic disease
dc.keywordsOligogenic inheritance
dc.keywordsMotor neuron disease
dc.language.isoeng
dc.publisherOxford Univ Press
dc.relation.grantnoKU Leuven; FWO-Vlaanderen [C1-C14-17-107]; IWT (Project MinE) [G0B2819N]; Belgian National Lottery; ALS Liga Belgie; Research Foundation-Flanders (FWO); Fund for Clinical Academic studies of the university hospitals of Leuven, Belgium [1164018N, 40900]; European Research Council (ERC) under the European Union [S61184]; Health~Holland, Top Sector Life Sciences Health [772376-EScORIAL]; ALS Foundation Netherlands
dc.relation.ispartofBrain
dc.subjectClinical neurology
dc.subjectNeurosciences
dc.titleGenetic variability in sporadic amyotrophic lateral sclerosis
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorBaşak, Ayşe Nazlı
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit1Research Center
local.publication.orgunit2KUTTAM (Koç University Research Center for Translational Medicine)
local.publication.orgunit2School of Medicine
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