{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:20Z","timestamp":1792787300311,"version":"4.5.0"},"reference-count":20,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T00:00:00Z","timestamp":1702684800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIHR Research Professorship","award":["RP-2016-07-011"],"award-info":[{"award-number":["RP-2016-07-011"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,11,5]]},"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are\n                      <jats:italic>C9orf72<\/jats:italic>\n                      ,\n                      <jats:italic>SOD1<\/jats:italic>\n                      ,\n                      <jats:italic>TARDBP<\/jats:italic>\n                      and\n                      <jats:italic>FUS<\/jats:italic>\n                      . Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for\n                      <jats:italic>C9orf72<\/jats:italic>\n                      were obtained from the published literature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for\n                      <jats:italic>C9orf72<\/jats:italic>\n                      (95% CI (20.9 to 53.2)), 54% for\n                      <jats:italic>SOD1<\/jats:italic>\n                      (95%\u2009CI (32.7 to 88.6)), 38% for\n                      <jats:italic>TARDBP<\/jats:italic>\n                      (95%\u2009CI (21.1 to 69.8)) and 19% for\n                      <jats:italic>FUS<\/jats:italic>\n                      (95%\u2009CI (13.0 to 28.4)).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2023-109580","type":"journal-article","created":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T13:20:20Z","timestamp":1702732820000},"page":"294-297","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Reduced penetrance of gene variants causing amyotrophic lateral sclerosis"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5154-6714","authenticated-orcid":false,"given":"Andrew G L","family":"Douglas","sequence":"first","affiliation":[{"name":"Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK"},{"name":"Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK"},{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Baralle","sequence":"additional","affiliation":[{"name":"Human Genetic and Genomics, University of Southampton, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,12,16]]},"reference":[{"key":"2025101710481516000_61.3.294.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1603471"},{"key":"2025101710481516000_61.3.294.2","doi-asserted-by":"publisher","DOI":"10.1159\/000351153"},{"key":"2025101710481516000_61.3.294.3","doi-asserted-by":"publisher","DOI":"10.3109\/17482960802566824"},{"key":"2025101710481516000_61.3.294.4","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2010.224501"},{"key":"2025101710481516000_61.3.294.5","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21580"},{"key":"2025101710481516000_61.3.294.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00414-2"},{"key":"2025101710481516000_61.3.294.7","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2016-315018"},{"key":"2025101710481516000_61.3.294.8","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyw061"},{"key":"2025101710481516000_61.3.294.9","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1001\/jamaneurol.2019.2044","article-title":"Lifetime risk and heritability of amyotrophic lateral sclerosis","volume":"76","author":"Ryan","year":"2019","journal-title":"JAMA Neurol"},{"key":"2025101710481516000_61.3.294.10","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.63.3.345"},{"key":"2025101710481516000_61.3.294.11","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr195"},{"key":"2025101710481516000_61.3.294.12","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1001\/jamaneurol.2022.5128","article-title":"Incidence of syndromes associated with frontotemporal lobar degeneration in 9 European countries","volume":"80","author":"Logroscino","year":"2023","journal-title":"JAMA Neurol"},{"key":"2025101710481516000_61.3.294.13","doi-asserted-by":"publisher","DOI":"10.3109\/09540261.2013.776523"},{"key":"2025101710481516000_61.3.294.14","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181bf997a"},{"key":"2025101710481516000_61.3.294.15","doi-asserted-by":"crossref","unstructured":"Carr JS , Sirkis DW , Yokoyama JS . 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