{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T02:47:21Z","timestamp":1784342841262,"version":"3.55.0"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","award":["Al Khleifat\/Oct21\/975\u2010799"],"award-info":[{"award-number":["Al Khleifat\/Oct21\/975\u2010799"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011776","name":"MND Scotland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011776","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017026","name":"Spastic Paraplegia Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L501529\/1"],"award-info":[{"award-number":["MR\/L501529\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R024804\/1"],"award-info":[{"award-number":["MR\/R024804\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["NIHR202421"],"award-info":[{"award-number":["NIHR202421"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009360","name":"King's College London","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009360","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2024,7]]},"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n \n Neurofilament heavy\u2010chain gene (\n NEFH<\/jats:italic>\n ) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still,\n NEFH<\/jats:italic>\n is commonly included in genetic screening panels worldwide. We therefore aimed to determine if\n NEFH<\/jats:italic>\n variants modify ALS risk.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta\u2010analyses of published case\u2013control studies reporting\n NEFH<\/jats:italic>\n variants, and variant analysis of\n NEFH<\/jats:italic>\n in Project MinE whole\u2010genome sequencing data.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Fixed\u2010effects meta\u2010analysis found that rare (MAF\u2009<1%) missense variants in the tail domain of\n NEFH<\/jats:italic>\n increase ALS risk (OR 4.55, 95% CI 2.13\u20139.71,\n p<\/jats:italic>\n \u2009<\u20090.0001). In Project MinE, ultrarare\n NEFH<\/jats:italic>\n variants increased ALS risk (OR 1.37 95% CI 1.14\u20131.63,\n p<\/jats:italic>\n \u2009=\u20090.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18\u20131.77,\n p<\/jats:italic>\n Madsen\u2013Browning<\/jats:sub>\n \u2009=\u20090.0007, p\n SKAT\u2010O<\/jats:sub>\n \u2009=\u20090.003). While in the tail domain, ultrarare (MAF\u2009<0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86\u20134.37,\n p<\/jats:italic>\n Madsen\u2013Browning<\/jats:sub>\n \u2009=\u20090.039), supporting the meta\u2010analysis results. Finally, several tail in\u2010frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation.\n <\/jats:p>\n <\/jats:sec>\n \n Interpretation<\/jats:title>\n \n We showed that\n NEFH<\/jats:italic>\n tail missense and in\u2010frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/acn3.52083","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T06:18:59Z","timestamp":1716358739000},"page":"1775-1786","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mutations in the tail and rod domains of the neurofilament heavy\u2010chain gene increase the risk of\n ALS<\/scp>"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1231-2880","authenticated-orcid":false,"given":"Heather","family":"Marriott","sequence":"first","affiliation":[{"name":"Department of Basic and Clinical Neuroscience Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London London SE5 8AF UK"},{"name":"Department of Biostatistics and Health Informatics Institute of Psychiatry, Psychology and Neuroscience, King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Spargo","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London London SE5 8AF UK"},{"name":"Department of Biostatistics and Health Informatics Institute of Psychiatry, Psychology and Neuroscience, King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7406-9831","authenticated-orcid":false,"given":"Ahmad","family":"Al Khleifat","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London London SE5 8AF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Science Ume\u00e5 University Ume\u00e5 SE\u2010901 85 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6977-2517","authenticated-orcid":false,"given":"Nazli A.","family":"Ba\u015fak","sequence":"additional","affiliation":[{"name":"Translational Medicine Research Center, NDAL, School of Medicine Koc University Istanbul 34450 Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Cooper\u2010Knock","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN) University of Sheffield Sheffield S10 2HQ UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Corcia","sequence":"additional","affiliation":[{"name":"UMR 1253, Universit\u00e9 de Tours, Inserm Tours 37044 France"},{"name":"Centre de r\u00e9f\u00e9rence sur la SLA, CHU de Tours Tours 37044 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Couratier","sequence":"additional","affiliation":[{"name":"Centre de r\u00e9f\u00e9rence sur la SLA, CHRU de Limoges Limoges France"},{"name":"UMR 1094, Universit\u00e9 de Limoges, Inserm Limoges 87025 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-0158","authenticated-orcid":false,"given":"Mamede","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Instituto de Fisiologia, Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina Universidade de Lisboa Lisbon 1649\u2010028 Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Drory","sequence":"additional","affiliation":[{"name":"Department of Neurology Tel\u2010Aviv Sourasky Medical Centre Tel\u2010Aviv 64239 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