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Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings represent the first large-scale, case\u2013control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jnnp-2024-335364","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T13:20:40Z","timestamp":1739452840000},"page":"928-936","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications"],"prefix":"10.1136","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5280-5017","authenticated-orcid":false,"given":"Alfredo","family":"Iacoangeli","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Health Informatics, King's College London, London, UK"},{"name":"Department of Basic and Clinical Neuroscience, King's College London, London, UK"},{"name":"Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia"},{"name":"Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison A","family":"Dilliott","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada"},{"name":"Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Al Khleifat","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, King's College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0094-5429","authenticated-orcid":false,"given":"Peter M","family":"Andersen","sequence":"additional","affiliation":[{"name":"Clinical Science, Neurosciences, Ume\u00e5 Universitet Medicinska Fakulteten, Umea, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6977-2517","authenticated-orcid":false,"given":"Nazl\u0131 A","family":"Ba\u015fak","sequence":"additional","affiliation":[{"name":"Suna and \u0130nan K\u0131ra\u00e7 Foundation, Neurodegeneration Research Laboratory (NDAL), KUTTAM, Ko\u00e7 University School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-8689","authenticated-orcid":false,"given":"Johnathan","family":"Cooper-Knock","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1625-8845","authenticated-orcid":false,"given":"Philippe","family":"Corcia","sequence":"additional","affiliation":[{"name":"UMR 1253, Universit\u00e9 de Tours, Inserm, Tours, France"},{"name":"Centre de r\u00e9f\u00e9rence sur la SLA, CHU de Tours, Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9562-856X","authenticated-orcid":false,"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, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-0158","authenticated-orcid":false,"given":"Mamede","family":"deCarvalho","sequence":"additional","affiliation":[{"name":"Instituto de Fisiologia, Universidade de 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M","family":"Lerner","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"name":"Department of Neurology, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2610-1291","authenticated-orcid":false,"given":"Orla","family":"Hardiman","sequence":"additional","affiliation":[{"name":"Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E","family":"Landers","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell L","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, Trinity College Dublin, Dublin, 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