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De novo mutations in SOD1 are a cause of ALS
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
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2022 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 93, p. 201-206Article in journal (Refereed) Published
Abstract [en]

Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS.

Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.

Results: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.

Conclusions:  De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.

Data availability statement: Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2022. Vol. 93, p. 201-206
Keywords [en]
Psychiatry and Mental health, Clinical Neurology, Surgery
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-189488DOI: 10.1136/jnnp-2021-327520ISI: 000722681900001Scopus ID: 2-s2.0-85120353083OAI: oai:DiVA.org:umu-189488DiVA, id: diva2:1610896
Funder
Konung Gustaf V:s och Drottning Victorias FrimurarestiftelseSwedish Association of Persons with Neurological DisabilitiesKnut and Alice Wallenberg Foundation, 2012.0091, 2014.0305, 2020.0232The Swedish Brain Foundation, 2012-0262, 2012-0305, 2013-0279, 2016-0303, 2020-0353Swedish Research Council, 2012-3167, 2017-03100Region VästerbottenAvailable from: 2021-11-12 Created: 2021-11-12 Last updated: 2023-03-24Bibliographically approved

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Nordin, AngelicaNordin, FridaForsberg, KarinAndersen, Peter Munch

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