{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:09:14Z","timestamp":1793225354231,"version":"4.5.0"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T00:00:00Z","timestamp":1649030400000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000866","name":"Cardiff University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000866","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L010305\/1"],"award-info":[{"award-number":["MR\/L010305\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L010305\/1"],"award-info":[{"award-number":["MR\/L010305\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P001629\/1"],"award-info":[{"award-number":["MR\/P001629\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000368","name":"Brain Research Trust","doi-asserted-by":"publisher","award":["201617-06"],"award-info":[{"award-number":["201617-06"]}],"id":[{"id":"10.13039\/501100000368","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004218","name":"Patrick Berthoud Charitable Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004218","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Neurosci"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The age at onset of motor symptoms in Huntington\u2019s disease (HD) is driven by\n                    <jats:italic>HTT<\/jats:italic>\n                    CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete\n                    <jats:italic>FAN1<\/jats:italic>\n                    knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.\n                  <\/jats:p>","DOI":"10.1038\/s41593-022-01033-5","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T05:33:05Z","timestamp":1649136785000},"page":"446-457","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["Exome sequencing of individuals with Huntington\u2019s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset"],"prefix":"10.1038","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6308-2136","authenticated-orcid":false,"given":"Branduff","family":"McAllister","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6699-0674","authenticated-orcid":false,"given":"Jasmine","family":"Donaldson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline S.","family":"Binda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6507-6079","authenticated-orcid":false,"given":"Sophie","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8110-7114","authenticated-orcid":false,"given":"Uroosa","family":"Chughtai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0767-385X","authenticated-orcid":false,"given":"Joseph","family":"Stone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3126-1903","authenticated-orcid":false,"given":"Sergey","family":"Lobanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Elliston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura-Nadine","family":"Schuhmacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliott","family":"Rees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6600-6507","authenticated-orcid":false,"given":"Georgina","family":"Menzies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-4080","authenticated-orcid":false,"given":"Marc","family":"Ciosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alastair","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Chao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7789-686X","authenticated-orcid":false,"given":"Eun Pyo","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Lucente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5799-0787","authenticated-orcid":false,"given":"Jong-Min","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcy E.","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7181-9652","authenticated-orcid":false,"given":"Jeffrey D.","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth H.","family":"Aylward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Bernhard","family":"Landwehrmeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E.","family":"Rosser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"REGISTRY Investigators of the European Huntington\u2019s disease network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane S.","family":"Paulsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"PREDICT-HD Investigators of the Huntington Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel M.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James F.","family":"Gusella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-8264","authenticated-orcid":false,"given":"Darren G.","family":"Monckton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4009-186X","authenticated-orcid":false,"given":"Nicholas D.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0870-9412","authenticated-orcid":false,"given":"Peter","family":"Holmans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-4612","authenticated-orcid":false,"given":"Lesley","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9804-2131","authenticated-orcid":false,"given":"Thomas H.","family":"Massey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,4]]},"reference":[{"key":"1033_CR1","doi-asserted-by":"publisher","first-page":"e2395","DOI":"10.1212\/WNL.0000000000011893","volume":"96","author":"B McAllister","year":"2021","unstructured":"McAllister, B. et al. Timing and impact of psychiatric, cognitive, and motor abnormalities in Huntington disease. Neurology 96, e2395\u2013e2406 (2021).","journal-title":"Neurology"},{"key":"1033_CR2","doi-asserted-by":"publisher","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","volume":"1","author":"GP Bates","year":"2015","unstructured":"Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Prim. 1, 15005 (2015).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"1033_CR3","doi-asserted-by":"crossref","unstructured":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. The Huntington\u2019s Disease Collaborative Research Group. Cell 72, 971\u2013983 (1993).","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"1033_CR4","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/ng0893-398","volume":"4","author":"SE Andrew","year":"1993","unstructured":"Andrew, S. E. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington\u2019s disease. Nat. Genet. 4, 398\u2013403 (1993).","journal-title":"Nat. Genet."},{"key":"1033_CR5","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/ng0893-387","volume":"4","author":"M Duyao","year":"1993","unstructured":"Duyao, M. et al. Trinucleotide repeat length instability and age of onset in Huntington\u2019s disease. Nat. Genet. 4, 387\u2013392 (1993).","journal-title":"Nat. Genet."},{"key":"1033_CR6","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/ng0893-393","volume":"4","author":"RG Snell","year":"1993","unstructured":"Snell, R. G. et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington\u2019s disease. Nat. Genet. 4, 393\u2013397 (1993).","journal-title":"Nat. Genet."},{"key":"1033_CR7","doi-asserted-by":"publisher","first-page":"3498","DOI":"10.1073\/pnas.0308679101","volume":"101","author":"NS Wexler","year":"2004","unstructured":"Wexler, N. S. et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington\u2019s disease age of onset. Proc. Natl Acad. Sci. USA 101, 3498\u20133503 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1033_CR8","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.cell.2019.06.036","volume":"178","author":"GeM-HD Consortium.","year":"2019","unstructured":"GeM-HD Consortium. CAG repeat not polyglutamine length determines timing of Huntington\u2019s disease onset. Cell 178, 887\u2013900 (2019).","journal-title":"Cell"},{"key":"1033_CR9","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/S1474-4422(17)30161-8","volume":"16","author":"DJH Moss","year":"2017","unstructured":"Moss, D. J. H. et al. Identification of genetic variants associated with Huntington\u2019s disease progression: a genome-wide association study. Lancet Neurol. 16, 701\u2013711 (2017).","journal-title":"Lancet Neurol."},{"key":"1033_CR10","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.cell.2015.07.003","volume":"162","author":"GeM-HD Consortium.","year":"2015","unstructured":"GeM-HD Consortium. Identification of genetic factors that modify clinical onset of Huntington\u2019s disease. Cell 162, 516\u2013526 (2015).","journal-title":"Cell"},{"key":"1033_CR11","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.cell.2010.06.021","volume":"142","author":"C MacKay","year":"2010","unstructured":"MacKay, C. et al. Identification of KIAA1018\/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell 142, 65\u201376 (2010).","journal-title":"Cell"},{"key":"1033_CR12","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1016\/j.ebiom.2019.09.020","volume":"48","author":"M Ciosi","year":"2019","unstructured":"Ciosi, M. et al. A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine 48, 568\u2013580 (2019).","journal-title":"EBioMedicine"},{"key":"1033_CR13","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.ajhg.2019.04.007","volume":"104","author":"GEB Wright","year":"2019","unstructured":"Wright, G. E. B. et al. Length of uninterrupted CAG, independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington disease. Am. J. Hum. Genet. 104, 1116\u20131126 (2019).","journal-title":"Am. J. Hum. Genet."},{"key":"1033_CR14","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1093\/hmg\/ddm054","volume":"16","author":"PF Shelbourne","year":"2007","unstructured":"Shelbourne, P. F. et al. Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Hum. Mol. Genet. 16, 1133\u20131142 (2007).","journal-title":"Hum. Mol. Genet."},{"key":"1033_CR15","doi-asserted-by":"publisher","first-page":"3467","DOI":"10.1073\/pnas.0800048105","volume":"105","author":"R Gonitel","year":"2008","unstructured":"Gonitel, R. et al. DNA instability in postmitotic neurons. Proc. Natl Acad. Sci. USA 105, 3467\u20133472 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1033_CR16","doi-asserted-by":"publisher","first-page":"e44273","DOI":"10.1371\/journal.pone.0044273","volume":"7","author":"M Kovalenko","year":"2012","unstructured":"Kovalenko, M. et al. Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington\u2019s disease knock-in mice. PLoS ONE 7, e44273 (2012).","journal-title":"PLoS ONE"},{"key":"1033_CR17","doi-asserted-by":"publisher","first-page":"3039","DOI":"10.1093\/hmg\/ddp242","volume":"18","author":"M Swami","year":"2009","unstructured":"Swami, M. et al. Somatic expansion of the Huntington\u2019s disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum. Mol. Genet. 18, 3039\u20133047 (2009).","journal-title":"Hum. Mol. Genet."},{"key":"1033_CR18","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.nbd.2008.09.014","volume":"33","author":"E Dragileva","year":"2009","unstructured":"Dragileva, E. et al. Intergenerational and striatal CAG repeat instability in Huntington\u2019s disease knock-in mice involve different DNA repair genes. Neurobiol. Dis. 33, 37\u201347 (2009).","journal-title":"Neurobiol. Dis."},{"key":"1033_CR19","doi-asserted-by":"publisher","first-page":"e1003930","DOI":"10.1371\/journal.pgen.1003930","volume":"9","author":"RM Pinto","year":"2013","unstructured":"Pinto, R. M. et al. Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington\u2019s disease mice: genome-wide and candidate approaches. PLoS Genet. 9, e1003930 (2013).","journal-title":"PLoS Genet."},{"key":"1033_CR20","doi-asserted-by":"publisher","first-page":"3044","DOI":"10.1093\/hmg\/ddaa196","volume":"29","author":"JM Loupe","year":"2020","unstructured":"Loupe, J. M. et al. Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington\u2019s disease knock-in mice is blocked by Mlh1 knock-out. Hum. Mol. Genet. 29, 3044\u20133053 (2020).","journal-title":"Hum. Mol. Genet."},{"key":"1033_CR21","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1126\/science.1222794","volume":"337","author":"MT Maurano","year":"2012","unstructured":"Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190\u20131195 (2012).","journal-title":"Science"},{"key":"1033_CR22","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.ajhg.2017.06.005","volume":"101","author":"PM Visscher","year":"2017","unstructured":"Visscher, P. M. et al. 10 years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 101, 5\u201322 (2017).","journal-title":"Am. J. Hum. Genet."},{"key":"1033_CR23","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/s41593-019-0565-2","volume":"23","author":"E Rees","year":"2020","unstructured":"Rees, E. et al. De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia. Nat. Neurosci. 23, 179\u2013184 (2020).","journal-title":"Nat. Neurosci."},{"key":"1033_CR24","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1002\/acn3.582","volume":"5","author":"NS Raghavan","year":"2018","unstructured":"Raghavan, N. S. et al. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer\u2019s disease. Ann. Clin. Transl. Neurol. 5, 832\u2013842 (2018).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"1033_CR25","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1038\/ng.3622","volume":"48","author":"W van Rheenen","year":"2016","unstructured":"van Rheenen, W. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat. Genet. 48, 1043\u20131048 (2016).","journal-title":"Nat. Genet."},{"key":"1033_CR26","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.1399-0004.2004.00241.x","volume":"65","author":"DR Langbehn","year":"2004","unstructured":"Langbehn, D. R., Brinkman, R. R., Falush, D., Paulsen, J. S. & Hayden, M. R. A new model for prediction of the age of onset and penetrance for Huntington\u2019s disease based on CAG length. Clin. Genet. 65, 267\u2013277 (2004).","journal-title":"Clin. Genet."},{"key":"1033_CR27","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1136\/jnnp.2007.128728","volume":"79","author":"JS Paulsen","year":"2008","unstructured":"Paulsen, J. S. et al. Detection of Huntington\u2019s disease decades before diagnosis: the Predict-HD study. J. Neurol. Neurosurg. Psychiatry 79, 874\u2013880 (2008).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"1033_CR28","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1093\/hmg\/ddy375","volume":"28","author":"R Goold","year":"2019","unstructured":"Goold, R. et al. FAN1 modifies Huntington\u2019s disease progression by stabilizing the expanded HTT CAG repeat. Hum. Mol. Genet. 28, 650\u2013661 (2019).","journal-title":"Hum. Mol. Genet."},{"key":"1033_CR29","doi-asserted-by":"publisher","first-page":"109649","DOI":"10.1016\/j.celrep.2021.109649","volume":"36","author":"R Goold","year":"2021","unstructured":"Goold, R. et al. FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington\u2019s disease. Cell Rep. 36, 109649 (2021).","journal-title":"Cell Rep."},{"key":"1033_CR30","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.ajhg.2020.05.012","volume":"107","author":"K-H Kim","year":"2020","unstructured":"Kim, K.-H. et al. Genetic and functional analyses point to FAN1 as the source of multiple Huntington disease modifier effects. Am. J. Hum. Genet. 107, 96\u2013110 (2020).","journal-title":"Am. J. Hum. Genet."},{"key":"1033_CR31","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1126\/science.aal4043","volume":"359","author":"L Bastarache","year":"2018","unstructured":"Bastarache, L. et al. Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. Science 359, 1233\u20131239 (2018).","journal-title":"Science"},{"key":"1033_CR32","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.stem.2012.04.027","volume":"11","author":"HD iPSC","year":"2012","unstructured":"iPSC, H. D. Consortium. Induced pluripotent stem cells from patients with Huntington\u2019s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11, 264\u2013278 (2012).","journal-title":"Cell Stem Cell"},{"key":"1033_CR33","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1093\/hmg\/ddv080","volume":"24","author":"VB Mattis","year":"2015","unstructured":"Mattis, V. B. et al. HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity. Hum. Mol. Genet. 24, 3257\u20133271 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"1033_CR34","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.cell.2010.06.022","volume":"142","author":"K Kratz","year":"2010","unstructured":"Kratz, K. et al. Deficiency of FANCD2-associated nuclease KIAA1018\/FAN1 sensitizes cells to interstrand crosslinking agents. Cell 142, 77\u201388 (2010).","journal-title":". Cell"},{"key":"1033_CR35","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1126\/science.1192656","volume":"329","author":"T Liu","year":"2010","unstructured":"Liu, T., Ghosal, G., Yuan, J., Chen, J. & Huang, J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science 329, 693\u2013696 (2010).","journal-title":"Science"},{"key":"1033_CR36","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.1093\/hmg\/ddg352","volume":"12","author":"L Kennedy","year":"2003","unstructured":"Kennedy, L. et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum. Mol. Genet. 12, 3359\u20133367 (2003).","journal-title":"Hum. Mol. Genet."},{"key":"1033_CR37","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.1093\/brain\/awz115","volume":"142","author":"M Flower","year":"2019","unstructured":"Flower, M. et al. MSH3 modifies somatic instability and disease severity in Huntington\u2019s and myotonic dystrophy type 1. Brain 142, 1876\u20131886 (2019).","journal-title":"Brain"},{"key":"1033_CR38","doi-asserted-by":"publisher","first-page":"12593","DOI":"10.1073\/pnas.0909087107","volume":"107","author":"GB Panigrahi","year":"2010","unstructured":"Panigrahi, G. B., Slean, M. M., Simard, J. P., Gileadi, O. & Pearson, C. E. Isolated short CTG\/CAG DNA slip-outs are repaired efficiently by hMutS\u03b2, but clustered slip-outs are poorly repaired. Proc. Natl Acad. Sci. USA 107, 12593\u201312598 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1033_CR39","first-page":"7087","volume":"24","author":"X-N Zhao","year":"2015","unstructured":"Zhao, X.-N. et al. Muts\u03b2 generates both expansions and contractions in a mouse model of the Fragile X-associated disorders. Hum. Mol. Genet. 24, 7087\u20137096 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"1033_CR40","doi-asserted-by":"publisher","first-page":"e1008902","DOI":"10.1371\/journal.pgen.1008902","volume":"16","author":"CJ Miller","year":"2020","unstructured":"Miller, C. J., Kim, G.-Y., Zhao, X. & Usdin, K. All three mammalian MutL complexes are required for repeat expansion in a mouse cell model of the Fragile X-related disorders. PLoS Genet. 16, e1008902 (2020).","journal-title":"PLoS Genet."},{"key":"1033_CR41","doi-asserted-by":"publisher","first-page":"32368","DOI":"10.1074\/jbc.274.45.32368","volume":"274","author":"M R\u00e4schle","year":"1999","unstructured":"R\u00e4schle, M., Marra, G., Nystr\u00f6m-Lahti, M., Sch\u00e4r, P. & Jiricny, J. Identification of hMutL\u03b2, a heterodimer of hMLH1 and hPMS1. J. Biol. Chem. 274, 32368\u201332375 (1999).","journal-title":"J. Biol. Chem."},{"key":"1033_CR42","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434\u2013443 (2020).","journal-title":"Nature"},{"key":"1033_CR43","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.molcel.2010.06.023","volume":"39","author":"A Smogorzewska","year":"2010","unstructured":"Smogorzewska, A. et al. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol. Cell 39, 36\u201347 (2010).","journal-title":"Mol. Cell"},{"key":"1033_CR44","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1101\/gad.276287.115","volume":"30","author":"C Lachaud","year":"2016","unstructured":"Lachaud, C. et al. Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice. Genes Dev. 30, 639\u2013644 (2016).","journal-title":"Genes Dev."},{"key":"1033_CR45","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.1074\/jbc.M609989200","volume":"282","author":"E Cannavo","year":"2007","unstructured":"Cannavo, E., Gerrits, B., Marra, G., Schlapbach, R. & Jiricny, J. Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2. J. Biol. Chem. 282, 2976\u20132986 (2007).","journal-title":"J. Biol. Chem."},{"key":"1033_CR46","doi-asserted-by":"publisher","first-page":"eabf7906","DOI":"10.1126\/sciadv.abf7906","volume":"7","author":"A Porro","year":"2021","unstructured":"Porro, A. et al. FAN1\u2013MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG\/CTG repeats. Sci. Adv. 7, eabf7906 (2021).","journal-title":"Sci. Adv."},{"key":"1033_CR47","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1002\/ana.24656","volume":"79","author":"C Bettencourt","year":"2016","unstructured":"Bettencourt, C. et al. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Ann. Neurol. 79, 983\u2013990 (2016).","journal-title":"Ann. Neurol."},{"key":"1033_CR48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.dnarep.2018.07.001","volume":"69","author":"X-N Zhao","year":"2018","unstructured":"Zhao, X.-N. & Usdin, K. FAN1 protects against repeat expansions in a Fragile X mouse model. DNA Repair (Amst). 69, 1\u20135 (2018).","journal-title":"DNA Repair (Amst)."},{"key":"1033_CR49","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/nature21039","volume":"542","author":"E Marouli","year":"2017","unstructured":"Marouli, E. et al. Rare and low-frequency coding variants alter human adult height. Nature 542, 186\u2013190 (2017).","journal-title":"Nature"},{"key":"1033_CR50","doi-asserted-by":"publisher","first-page":"e1007274","DOI":"10.1371\/journal.pgen.1007274","volume":"14","author":"MJ Chao","year":"2018","unstructured":"Chao, M. J. et al. Population-specific genetic modification of Huntington\u2019s disease in Venezuela. PLoS Genet. 14, e1007274 (2018).","journal-title":"PLoS Genet."},{"key":"1033_CR51","doi-asserted-by":"publisher","first-page":"D506","DOI":"10.1093\/nar\/gky1049","volume":"47","author":"UniProt Consortium.","year":"2019","unstructured":"UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 47, D506\u2013D515 (2019).","journal-title":"Nucleic Acids Res."},{"key":"1033_CR52","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.dnarep.2017.06.016","volume":"56","author":"H Jin","year":"2017","unstructured":"Jin, H. & Cho, Y. Structural and functional relationships of FAN1. DNA Repair (Amst). 56, 135\u2013143 (2017).","journal-title":"DNA Repair (Amst)."},{"key":"1033_CR53","first-page":"RRN1184","volume":"2","author":"M Orth","year":"2010","unstructured":"Orth, M. et al. Observing Huntington\u2019s disease: the European Huntington\u2019s Disease Network\u2019s REGISTRY. PLoS Curr. 2, RRN1184 (2010).","journal-title":"PLoS Curr."},{"key":"1033_CR54","unstructured":"Cleveland, W., Grosse, E. & Shyu, W. Local regression models. In: Statistical Models in S, Chapter 8 (Chapman and Hall\/CRC, 1991)."},{"key":"1033_CR55","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1002\/ajmg.b.31232","volume":"156B","author":"Y Zhang","year":"2011","unstructured":"Zhang, Y. et al. Indexing disease progression at study entry with individuals at-risk for Huntington disease. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 751\u2013763 (2011).","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"1033_CR56","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1214\/08-AOAS169","volume":"2","author":"H Ishwaran","year":"2008","unstructured":"Ishwaran, H., Kogalur, U. B., Blackstone, E. H. & Lauer, M. S. Random survival forests. Ann. Appl. Stat. 2, 841\u2013860 (2008).","journal-title":"Ann. Appl. Stat."},{"key":"1033_CR57","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-13-152","volume":"13","author":"P Royston","year":"2013","unstructured":"Royston, P. & Parmar, M. K. B. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med. Res. Methodol. 13, 152 (2013).","journal-title":"BMC Med. Res. Methodol."},{"key":"1033_CR58","doi-asserted-by":"publisher","unstructured":"Ciosi, M. et al. Library preparation and MiSeq sequencing for the genotyping-by-sequencing of the Huntington disease HTT exon one trinucleotide repeat and the quantification of somatic mosaicism. Protocol Exchange. https:\/\/doi.org\/10.1038\/protex.2018.089 (2018).","DOI":"10.1038\/protex.2018.089"},{"key":"1033_CR59","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1093\/bib\/bbs012","volume":"14","author":"I Milne","year":"2013","unstructured":"Milne, I. et al. Using Tablet for visual exploration of second-generation sequencing data. Brief. Bioinform. 14, 193\u2013202 (2013).","journal-title":"Brief. Bioinform."},{"key":"1033_CR60","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. et al. The Sequence Alignment\/Map format and SAMtools. Bioinformatics 25, 2078\u20132079 (2009).","journal-title":"Bioinformatics"},{"key":"1033_CR61","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nbt.1523","volume":"27","author":"A Gnirke","year":"2009","unstructured":"Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat. Biotechnol. 27, 182\u2013189 (2009).","journal-title":"Nat. Biotechnol."},{"key":"1033_CR62","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-1-r1","volume":"12","author":"S Fisher","year":"2011","unstructured":"Fisher, S. et al. A scalable, fully automated process for construction of sequence-ready human exome targeted capture libraries. Genome Biol. 12, R1 (2011).","journal-title":"Genome Biol."},{"key":"1033_CR63","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1126\/science.1258973","volume":"346","author":"R Wang","year":"2014","unstructured":"Wang, R. et al. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1. Science 346, 1127\u20131130 (2014).","journal-title":"Science"},{"key":"1033_CR64","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.dnarep.2018.02.007","volume":"64","author":"T Rao","year":"2018","unstructured":"Rao, T. et al. Importance of homo-dimerization of Fanconi-associated nuclease 1 in DNA flap cleavage. DNA Repair (Amst). 64, 53\u201358 (2018).","journal-title":"DNA Repair (Amst)."},{"key":"1033_CR65","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-4939-8666-8_1","volume":"1833","author":"L Fang","year":"2018","unstructured":"Fang, L. & Wang, K. Identification of copy number variants from SNP arrays using PennCNV. Methods Mol. Biol. 1833, 1\u201328 (2018).","journal-title":"Methods Mol. Biol."},{"key":"1033_CR66","doi-asserted-by":"publisher","first-page":"C520","DOI":"10.1152\/ajpcell.00166.2015","volume":"310","author":"V Telezhkin","year":"2016","unstructured":"Telezhkin, V. et al. Forced cell cycle exit and modulation of GABAA, CREB, and GSK3\u03b2 signaling promote functional maturation of induced pluripotent stem cell-derived neurons. Am. J. Physiol. Cell Physiol. 310, C520\u2013C541 (2016).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"1033_CR67","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.stemcr.2020.01.015","volume":"14","author":"C Smith-Geater","year":"2020","unstructured":"Smith-Geater, C. et al. Aberrant development corrected in adult-onset Huntington\u2019s disease iPSC-derived neuronal cultures via WNT signaling modulation. Stem Cell Rep. 14, 406\u2013419 (2020).","journal-title":"Stem Cell Rep."},{"key":"1033_CR68","doi-asserted-by":"publisher","DOI":"10.1186\/s12863-016-0365-6","volume":"17","author":"G Covarrubias-Pazaran","year":"2016","unstructured":"Covarrubias-Pazaran, G., Diaz-Garcia, L., Schlautman, B., Salazar, W. & Zalapa, J. Fragman: an R package for fragment analysis. BMC Genet. 17, 62 (2016).","journal-title":"BMC Genet."},{"key":"1033_CR69","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-4-29","volume":"4","author":"J-M Lee","year":"2010","unstructured":"Lee, J.-M. et al. A novel approach to investigate tissue-specific trinucleotide repeat instability. BMC Syst. Biol. 4, 29 (2010).","journal-title":"BMC Syst. Biol."},{"key":"1033_CR70","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","volume":"43","author":"MA DePristo","year":"2011","unstructured":"DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491\u2013498 (2011).","journal-title":"Nat. Genet."},{"key":"1033_CR71","doi-asserted-by":"crossref","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","volume":"43","author":"GA Van der Auwera","year":"2013","unstructured":"Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 43, 11.10.1\u201311.10.33 (2013).","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"1033_CR72","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297\u20131303 (2010).","journal-title":"Genome Res."},{"key":"1033_CR73","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows\u2013Wheeler transform. Bioinformatics 25, 1754\u20131760 (2009).","journal-title":"Bioinformatics"},{"key":"1033_CR74","doi-asserted-by":"crossref","unstructured":"Poplin, R. et al. Scaling accurate genetic variant discovery to tens of thousands of samples. Preprint at https:\/\/www.biorxiv.org\/content\/10.1101\/201178v3 (2018).","DOI":"10.1101\/201178"},{"key":"1033_CR75","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.ajhg.2012.09.004","volume":"91","author":"G Jun","year":"2012","unstructured":"Jun, G. et al. Detecting and estimating contamination of human DNA samples in sequencing and array-based genotype data. Am. J. Hum. Genet. 91, 839\u2013848 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"1033_CR76","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285\u2013291 (2016).","journal-title":"Nature"},{"key":"1033_CR77","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.ajhg.2017.01.017","volume":"100","author":"BS Pedersen","year":"2017","unstructured":"Pedersen, B. S. & Quinlan, A. R. Who\u2019s who? Detecting and resolving sample anomalies in human DNA sequencing studies with Peddy. Am. J. Hum. Genet. 100, 406\u2013413 (2017).","journal-title":"Am. J. Hum. Genet."},{"key":"1033_CR78","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"1000 Genomes Project Consortium.","year":"2015","unstructured":"1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68\u201374 (2015).","journal-title":"Nature"},{"key":"1033_CR79","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1002\/humu.21517","volume":"32","author":"X Liu","year":"2011","unstructured":"Liu, X., Jian, X. & Boerwinkle, E. dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum. Mutat. 32, 894\u2013899 (2011).","journal-title":"Hum. Mutat."},{"key":"1033_CR80","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/humu.22932","volume":"37","author":"X Liu","year":"2016","unstructured":"Liu, X., Wu, C., Li, C. & Boerwinkle, E. dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum. Mutat. 37, 235\u2013241 (2016).","journal-title":"Hum. Mutat."},{"key":"1033_CR81","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren, W. et al. The Ensembl Variant Effect Predictor. Genome Biol. 17, 122 (2016).","journal-title":"Genome Biol."},{"key":"1033_CR82","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","volume":"46","author":"M Kircher","year":"2014","unstructured":"Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310\u2013315 (2014).","journal-title":"Nat. Genet."},{"key":"1033_CR83","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.ajhg.2012.06.007","volume":"91","author":"S Lee","year":"2012","unstructured":"Lee, S. et al. Optimal unified approach for rare-variant association testing with application to small-sample case\u2013control whole-exome sequencing studies. Am. J. Hum. Genet. 91, 224\u2013237 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"1033_CR84","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.ajhg.2011.05.029","volume":"89","author":"MC Wu","year":"2011","unstructured":"Wu, M. C. et al. Rare-variant association testing for sequencing data with the sequence kernel association test. Am. J. Hum. Genet. 89, 82\u201393 (2011).","journal-title":"Am. J. Hum. Genet."}],"container-title":["Nature Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41593-022-01033-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-022-01033-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-022-01033-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T11:35:20Z","timestamp":1675164920000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41593-022-01033-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4]]},"references-count":84,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["1033"],"URL":"https:\/\/doi.org\/10.1038\/s41593-022-01033-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.13.439716","asserted-by":"object"}]},"ISSN":["1097-6256","1546-1726"],"issn-type":[{"value":"1097-6256","type":"print"},{"value":"1546-1726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4]]},"assertion":[{"value":"6 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"V.C.W. is a scientific advisory board member of Triplet Therapeutics, a company developing new therapeutic approaches to address triplet repeat disorders such Huntington\u2019s disease and myotonic dystrophy. V.C.W.\u2019s financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. V.C.W. is also a scientific advisory board member of LoQus23 Therapeutics and has provided paid consulting services to Alnylam. J.-M.L. is on the scientific advisory board of GenEdit. J.D.L. is a paid advisory board member for F. Hoffmann-La Roche and uniQure biopharma and is a paid consultant for Vaccinex, Wave Life Sciences, Genentech, Triplet Therapeutics and PTC Therapeutics. E.H.A. serves on a Data Safety Monitoring Board for Roche. G.B.L. has provided consulting services, advisory board functions, clinical trial services and\/or lectures for Allergan, Alnylam, Amarin, AOP Orphan Pharmaceuticals, Bayer Pharma, the CHDI Foundation, GlaxoSmithKline, F. Hoffmann-La Roche, Ipsen, Isis Pharma, Lundbeck, Neurosearch, Medesis, Medivation, Medtronic, NeuraMetrix, Novartis, Pfizer, Prana Biotechnology, Sangamo\/Shire, Siena Biotech, Temmler Pharma and Teva Pharmaceuticals. G.B.L. has also received research grant support from the CHDI Foundation, the Bundesministerium f\u00fcr Bildung und Forschung, the Deutsche Forschungsgemeinschaft and the European Commission (EU-FP7, JPND). His study site in Ulm has received compensation in the context of the observational Enroll-HD Study from Teva, Isis, F. Hoffmann-Roche and the Gossweiler Foundation. He receives royalties from Oxford University Press and is employed by the State of Baden-W\u00fcrttemberg at the University of Ulm. A.E.R. is chair of the European Huntington\u2019s Disease Network executive committee and is the global PI for Triplet Therapeutics. J.S.P. has provided consulting services, advisory board functions and clinical trial services for Acadia, F. Hoffman-La Roche, Wave Life Sciences and the CHDI Foundation. J.F.G. is a scientific advisory board member and has a financial interest in Triplet Therapeutics. His National Institutes of Health-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in Huntington\u2019s disease. The company is developing new therapeutic approaches to address triplet repeat disorders, such Huntington\u2019s disease, myotonic dystrophy and spinocerebellar ataxias. His interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. has also been a consultant for Wave Life Sciences. Within the last 5 years, D.G.M. has been a scientific consultant and\/or received honoraria\/stock options\/research contracts from AMO Pharma, Charles River Laboratories, LoQus23, Small Molecule RNA, Triplet Therapeutics and Vertex Pharmaceuticals. L.J. is a member of the scientific advisory boards of LoQus23 Therapeutics and Triplet Therapeutics. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics. B.M., J.D., C.S.B., S.P., U.C., G.E., J.S., S.L., L.E., L.-N.S., E.R., G.M., M.C., A.M., M.J.C., E.P.H., D.L., M.E.M., N.M.W., N.D.A. and P.H. have nothing to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}