Genetic variability in sporadic amyotrophic lateral sclerosis
| Autor(a) principal: | |
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| Data de Publicação: | 2023 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/59915 |
Resumo: | © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
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Genetic variability in sporadic amyotrophic lateral sclerosisComplex genetic diseaseMotor neuron diseaseOligogenic inheritance© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comWith 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 × 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.This 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 België. 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 from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no 772376—EScORIAL)Oxford University PressRepositório da Universidade de LisboaVan Daele, Sien HildeMoisse, Matthieuvan Vugt, Joke J. F. A.Zwamborn, Ramona A. J.van der Spek, Rickvan Rheenen, WouterVan Eijk, KristelKenna, KevinCorcia, PhilippeVourc'h, PatrickCouratier, PhilippeHardiman, OrlaMcLaughin, RussellGotkine, MarcDrory, VivianTicozzi, NicolaSilani, VincenzoRatti, AntoniaCarvalho, MamedeMora Pardina, Jesús S.Povedano, MonicaAndersen, Peter M.Weber, MarkusBaşak, Nazli A.Shaw, ChrisShaw, Pamela J.Morrison, Karen E.Landers, John E.Glass, Jonathan D.van Es, Michael A.van den Berg, Leonard H.Al-Chalabi, AmmarVeldink, JanVan Damme, Philip2023-10-20T14:03:51Z20232023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/59915engBrain. 2023 Sep 1;146(9):3760-37690006-895010.1093/brain/awad1201460-2156info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:09:18Zoai:repositorio.ul.pt:10451/59915Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:09:43.453452Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Genetic variability in sporadic amyotrophic lateral sclerosis |
| title |
Genetic variability in sporadic amyotrophic lateral sclerosis |
| spellingShingle |
Genetic variability in sporadic amyotrophic lateral sclerosis Van Daele, Sien Hilde Complex genetic disease Motor neuron disease Oligogenic inheritance |
| title_short |
Genetic variability in sporadic amyotrophic lateral sclerosis |
| title_full |
Genetic variability in sporadic amyotrophic lateral sclerosis |
| title_fullStr |
Genetic variability in sporadic amyotrophic lateral sclerosis |
| title_full_unstemmed |
Genetic variability in sporadic amyotrophic lateral sclerosis |
| title_sort |
Genetic variability in sporadic amyotrophic lateral sclerosis |
| author |
Van Daele, Sien Hilde |
| author_facet |
Van Daele, Sien Hilde Moisse, Matthieu van Vugt, Joke J. F. A. Zwamborn, Ramona A. J. van der Spek, Rick van Rheenen, Wouter Van Eijk, Kristel Kenna, Kevin Corcia, Philippe Vourc'h, Patrick Couratier, Philippe Hardiman, Orla McLaughin, Russell Gotkine, Marc Drory, Vivian Ticozzi, Nicola Silani, Vincenzo Ratti, Antonia Carvalho, Mamede Mora Pardina, Jesús S. Povedano, Monica Andersen, Peter M. Weber, Markus Başak, Nazli A. Shaw, Chris Shaw, Pamela J. Morrison, Karen E. Landers, John E. Glass, Jonathan D. van Es, Michael A. van den Berg, Leonard H. Al-Chalabi, Ammar Veldink, Jan Van Damme, Philip |
| author_role |
author |
| author2 |
Moisse, Matthieu van Vugt, Joke J. F. A. Zwamborn, Ramona A. J. van der Spek, Rick van Rheenen, Wouter Van Eijk, Kristel Kenna, Kevin Corcia, Philippe Vourc'h, Patrick Couratier, Philippe Hardiman, Orla McLaughin, Russell Gotkine, Marc Drory, Vivian Ticozzi, Nicola Silani, Vincenzo Ratti, Antonia Carvalho, Mamede Mora Pardina, Jesús S. Povedano, Monica Andersen, Peter M. Weber, Markus Başak, Nazli A. Shaw, Chris Shaw, Pamela J. Morrison, Karen E. Landers, John E. Glass, Jonathan D. van Es, Michael A. van den Berg, Leonard H. Al-Chalabi, Ammar Veldink, Jan Van Damme, Philip |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Van Daele, Sien Hilde Moisse, Matthieu van Vugt, Joke J. F. A. Zwamborn, Ramona A. J. van der Spek, Rick van Rheenen, Wouter Van Eijk, Kristel Kenna, Kevin Corcia, Philippe Vourc'h, Patrick Couratier, Philippe Hardiman, Orla McLaughin, Russell Gotkine, Marc Drory, Vivian Ticozzi, Nicola Silani, Vincenzo Ratti, Antonia Carvalho, Mamede Mora Pardina, Jesús S. Povedano, Monica Andersen, Peter M. Weber, Markus Başak, Nazli A. Shaw, Chris Shaw, Pamela J. Morrison, Karen E. Landers, John E. Glass, Jonathan D. van Es, Michael A. van den Berg, Leonard H. Al-Chalabi, Ammar Veldink, Jan Van Damme, Philip |
| dc.subject.por.fl_str_mv |
Complex genetic disease Motor neuron disease Oligogenic inheritance |
| topic |
Complex genetic disease Motor neuron disease Oligogenic inheritance |
| description |
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
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2023 |
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2023-10-20T14:03:51Z 2023 2023-01-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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http://hdl.handle.net/10451/59915 |
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eng |
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eng |
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Brain. 2023 Sep 1;146(9):3760-3769 0006-8950 10.1093/brain/awad120 1460-2156 |
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Oxford University Press |
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Oxford University Press |
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