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Sökning: onr:"swepub:oai:DiVA.org:umu-214248" > Genetic variability...

Genetic variability in sporadic amyotrophic lateral sclerosis

Van Daele, Sien Hilde (författare)
Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium; Department of Human genetics, University Hospitals Leuven, Leuven, Belgium
Moisse, Matthieu (författare)
Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium
van Vugt, Joke J F A (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
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Zwamborn, Ramona A J (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
van der Spek, Rick (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
van Rheenen, Wouter (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
Van Eijk, Kristel (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
Kenna, Kevin (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
Corcia, Philippe (författare)
Centre SLA, CHRU de Tours, Tours, France; UMR 1253, Université de Tours, Inserm, Tours, France
Vourc'h, Patrick (författare)
UMR 1253, Université de Tours, Inserm, Tours, France
Couratier, Philippe (författare)
Centre SLA, CHU Limoges, Limoges, France
Hardiman, Orla (författare)
Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Republic of Ireland, Dublin, United States
McLaughin, Russell (författare)
Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Republic of Ireland, Dublin, United States
Gotkine, Marc (författare)
Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
Drory, Vivian (författare)
Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel Aviv, Israel
Ticozzi, Nicola (författare)
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy
Silani, Vincenzo (författare)
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy
Ratti, Antonia (författare)
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano, Italy
de Carvalho, Mamede (författare)
Instituto de Fisiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Mora Pardina, Jesús S (författare)
ALS Unit, Hospital University San Rafael, Madrid, Spain
Povedano, Monica (författare)
Servei de Neurologia, Barcelona, Spain
Andersen, Peter M., 1962- (författare)
Umeå universitet,Neurovetenskaper
Weber, Markus (författare)
Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland
Başak, Nazli A. (författare)
Koç University, School of Medicine, Istanbul, Turkey
Shaw, Chris (författare)
Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, United Kingdom
Shaw, Pamela J. (författare)
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
Morrison, Karen E. (författare)
School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
Landers, John E. (författare)
Department of Neurology, University of Massachusetts Medical School, Worcester, United States
Glass, Jonathan D. (författare)
Department Neurology, Emory University School of Medicine, Atlanta, United States
van Es, Michael A. (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
van den Berg, Leonard H. (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
Al-Chalabi, Ammar (författare)
Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, United Kingdom
Veldink, Jan (författare)
Department of Neurology, UMC Utrecht Brain Center, Utrecht University, CX Utrecht, Netherlands
Van Damme, Philip (författare)
Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium
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 (creator_code:org_t)
Oxford University Press, 2023
2023
Engelska.
Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 146:9, s. 3760-3769
Relaterad länk:
https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

complex genetic disease
motor neuron disease
oligogenic inheritance

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