Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis.

Autor:	Ruf WP; Department of Neurology, Ulm University, Ulm 89081, Germany., Boros M; Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm 89081, Germany., Freischmidt A; Department of Neurology, Ulm University, Ulm 89081, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Ulm 89081, Germany., Brenner D; Department of Neurology, Ulm University, Ulm 89081, Germany., Grozdanov V; Department of Neurology, Ulm University, Ulm 89081, Germany., de Meirelles J; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Ulm 89081, Germany., Meyer T; Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin 13353, Germany., Grehl T; Department of Neurology, Alfried Krupp Hospital, Essen 45131, Germany., Petri S; Department of Neurology, Medizinische Hochschule Hannover, Hannover 30625, Germany., Grosskreutz J; Precision Neurology, University of Luebeck, Luebeck 23562, Germany., Weyen U; Department of Neurology, University Hospital Bochum, Bochum 44789, Germany., Guenther R; Department of Neurology, Technische Universität Dresden, Dresden 01307, Germany., Regensburger M; Department of Neurology, University Hospital Erlangen, Erlangen 91054, Germany., Hagenacker T; Department of Neurology Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, Essen 45147, Germany., Koch JC; Department of Neurology, University Medical Center Goettingen, Goettingen 37075, Germany., Emmer A; University Clinic and Polyclinic for Neurology, University Hospital Halle, Halle 06120, Germany., Roediger A; Department of Neurology, University Hospital Jena, Jena 07747, Germany., Steinbach R; Department of Neurology, University Hospital Jena, Jena 07747, Germany., Wolf J; Department of Neurology, Diako Mannheim, Mannheim 68163, Germany., Weishaupt JH; Department of Neurology, University Hospital Mannheim, Mannheim 68167, Germany., Lingor P; Department of Neurology, Technical University Munich, Munich 80333, Germany., Deschauer M; Department of Neurology, Technical University Munich, Munich 80333, Germany., Cordts I; Department of Neurology, Technical University Munich, Munich 80333, Germany., Klopstock T; Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-University, München 80336, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Munich 81377, Germany., Reilich P; Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-University, München 80336, Germany., Schoeberl F; Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-University, München 80336, Germany., Schrank B; Department of Neurology, DKD Helios Clinics, Wiesbaden 65191, Germany., Zeller D; Department of Neurology, University Hospital Wuerzburg, Wuerzburg 97080, Germany., Hermann A; Translational Neurodegeneration Section 'Albrecht Kossel', University Medical Center Rostock, Rostock 18146, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Rostock/Greifswald 17489, Germany., Knehr A; Department of Neurology, Ulm University, Ulm 89081, Germany., Günther K; Department of Neurology, Ulm University, Ulm 89081, Germany., Dorst J; Department of Neurology, Ulm University, Ulm 89081, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Ulm 89081, Germany., Schuster J; Department of Neurology, Ulm University, Ulm 89081, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Ulm 89081, Germany., Siebert R; Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm 89081, Germany., Ludolph AC; Department of Neurology, Ulm University, Ulm 89081, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), German Center for Neurodegenerative Diseases, Ulm 89081, Germany., Müller K; Department of Neurology, Ulm University, Ulm 89081, Germany.; Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm 89081, Germany.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2023 May 09; Vol. 5 (3), pp. fcad152. Date of Electronic Publication: 2023 May 09 (Print Publication: 2023).
DOI:	10.1093/braincomms/fcad152
Abstrakt:	Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02-2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12-0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling. Competing Interests: The authors report no competing interests. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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