{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:14:42Z","timestamp":1792682082676,"version":"4.5.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Up to 80% of rare disease patients remain undiagnosed after genomic\nsequencing\n                    <jats:sup>1<\/jats:sup>\n                    , with many probably involving pathogenic variants\nin yet to be discovered disease\u2013gene associations. To search for such\nassociations, we developed a rare variant gene burden analytical framework for\nMendelian diseases, and applied it to protein-coding variants from whole-genome\nsequencing of 34,851 cases and their family members recruited to the 100,000 Genomes\nProject\n                    <jats:sup>2<\/jats:sup>\n                    . A total of 141 new associations were identified,\nincluding five for which independent disease\u2013gene evidence was recently\npublished. Following in silico triaging and clinical expert review, 69 associations\nwere prioritized, of which 30 could be linked to existing experimental evidence. The\nfive associations with strongest overall genetic and experimental evidence were\nmonogenic diabetes with the known \u03b2 cell regulator\n                    <jats:sup>3,4<\/jats:sup>\n                    <jats:italic>UNC13A<\/jats:italic>\n                    , schizophrenia with\n                    <jats:italic>GPR17<\/jats:italic>\n                    , epilepsy with\n                    <jats:italic>RBFOX3<\/jats:italic>\n                    , Charcot\u2013Marie\u2013Tooth disease with\n                    <jats:italic>ARPC3<\/jats:italic>\n                    and anterior segment ocular abnormalities with\n                    <jats:italic>POMK<\/jats:italic>\n                    . Further confirmation of these and other\nassociations could lead to numerous diagnoses, highlighting the clinical impact of\nlarge-scale statistical approaches to rare disease\u2013gene association\ndiscovery.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-08623-w","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T11:04:10Z","timestamp":1740567850000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Rare disease gene association discovery in the 100,000 Genomes\nProject"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0839-9955","authenticated-orcid":false,"given":"Valentina","family":"Cipriani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0008-936X","authenticated-orcid":false,"given":"Letizia","family":"Vestito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0699-6411","authenticated-orcid":false,"given":"Emma F.","family":"Magavern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3265-1591","authenticated-orcid":false,"given":"Julius O. 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The editors are investigating these concerns and appropriate editorial action will be taken once this matter is resolved.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare the following competing interests: D.S. and\nM.C. were seconded to, and received salary from, Genomics England, a wholly\nowned Department of Health and Social Care company, from 2016 to 2018 and 2013\nto 2021, respectively. E.A.O. has research funding from Kamari Pharma, Pavella\nTherapeutics, Unilever and the Leo Foundation unrelated to this work. She is CI\nfor a trial for Kamari Pharma and performs consultancy for Kamari Pharma, Azitra\nand Palvella Therapeutics (all money goes to the university). S.L.Z. has\nprovided consultancy services to Health Lumen. All other authors declare no\ncompeting interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}