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Med."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the\n                    <jats:italic>C9orf72<\/jats:italic>\n                    gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the\n                    <jats:italic>VCP<\/jats:italic>\n                    gene and insertion in the\n                    <jats:italic>ERBB4<\/jats:italic>\n                    gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured\n                    <jats:italic>ERBB4<\/jats:italic>\n                    insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.\n                  <\/jats:p>","DOI":"10.1038\/s41525-021-00267-9","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T06:03:34Z","timestamp":1643349814000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7406-9831","authenticated-orcid":false,"given":"Ahmad","family":"Al Khleifat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Iacoangeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joke J. 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J.H.V. is a consultant for Biogen. L.H.V.D.B. reports grants from Netherlands ALS Foundation, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community\u2019s Health Seventh Framework Programme (grant agreement no. 259867 (EuroMOTOR)), grants from The Netherlands Organization for Health Research and Development)the STRENGTH project, funded through the EU Joint Programme \u2013 Neurodegenerative Disease Research, JPND), during the conduct of the study; personal fees from Calico, personal fees from Cytokinetics, grants and personal fees from Takeda, non-financial support from Orion, non-financial support from Orphazyme, outside the submitted work. CES reports grants from Avexis, grants from Eli Lilly, grants from Chronos Therapeutics, grants from Vertex Pharmaceuticals, during the conduct of the study; grants from QurAlis, grants from Chronos Therapeutics, grants from Biogen, outside the submitted work. A.A.K., O.H., M.P.P., J.S.M., P.J.S., J.E.L., C.E.S., N.B., O.H., W.R., P.V.D., N.B., K.K., B.K., H.B., and L.H.V.B. declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8"}}