{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:23:23Z","timestamp":1792790603425,"version":"4.5.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Ministry of Economy and Competitiveness | Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FIS PI15\/02227"],"award-info":[{"award-number":["FIS PI15\/02227"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Enroll-HD Departamento de Salud, Gobierno de Navarra","id":[{"id":"https:\/\/ror.org\/025qq4838","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Hum Genet"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Huntington disease (HD) is a neurodegenerative disorder caused by \u226536 CAGs in the\n                    <jats:italic>HTT<\/jats:italic>\n                    gene. Intermediate alleles (IAs) (27\u201335 CAGs) are not considered HD-causing, but their potential association with neurocognitive symptoms remains controversial. As\n                    <jats:italic>HTT<\/jats:italic>\n                    somatic CAG expansion influences HD onset, we hypothesised that IAs are somatically unstable, and that somatic CAG expansion may drive phenotypic presentation in some IA carriers. We quantified\n                    <jats:italic>HTT<\/jats:italic>\n                    somatic CAG expansions by MiSeq sequencing in the blood DNA of 164 HD subjects and 191 IA (symptomatic and control) carriers, and in the brain DNA of a symptomatic 33 CAG carrier. We also performed genotype-phenotype analysis. The phenotype of symptomatic IA carriers was characterised by motor (85%), cognitive (27%) and\/or behavioural (29%) signs, with a late (58.7\u2009\u00b1\u200918.6 years), but not CAG-dependent, age at onset. IAs displayed somatic expansion that were CAG and age-dependent in blood DNA, with 0.4% and 0.01% of DNA molecules expanding by CAG and year, respectively. Somatic expansions of +1 and +2 CAGs were detected in the brain of the individual with 33 CAGs, with the highest expansion frequency in the putamen (10.3%) and the lowest in the cerebellum (4.8%). Somatic expansion in blood DNA was not different in symptomatic vs. control IA carriers. In conclusion, we show that\n                    <jats:italic>HTT<\/jats:italic>\n                    IAs are somatically unstable, but we found no association with HD-like phenotypes. It is plausible, however, that some IAs, close to the HD pathological threshold and with a predisposing genetic background, could manifest with neurocognitive symptoms.\n                  <\/jats:p>","DOI":"10.1038\/s41431-024-01546-6","type":"journal-article","created":{"date-parts":[[2024,3,3]],"date-time":"2024-03-03T23:10:18Z","timestamp":1709507418000},"page":"770-778","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-465X","authenticated-orcid":false,"given":"Ainara","family":"Ruiz de Sabando","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ciosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkaitz","family":"Galbete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-3660","authenticated-orcid":false,"given":"Sarah A.","family":"Cumming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Spanish HD Collaborative Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"\u00c1lvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asunci\u00f3n","family":"Martinez-Descals","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Mila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jos\u00e9","family":"Trujillo-Tiebas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Luis","family":"L\u00f3pez-Send\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Fenollar-Cort\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Legarda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bernal Noguera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Mill\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camen","family":"Dur\u00e1n-Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Ruiz-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeca","family":"Ruiz Onandi","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\/0000-0002-7171-9202","authenticated-orcid":false,"given":"Maria A.","family":"Ramos-Arroyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"1546_CR1","first-page":"16","volume":"59","author":"DC Rubinsztein","year":"1996","unstructured":"Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996;59:16\u201322. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/8659522.","journal-title":"Am J Hum Genet"},{"key":"1546_CR2","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1136\/jmedgenet-2013-101796","volume":"50","author":"A Semaka","year":"2013","unstructured":"Semaka A, Kay C, Doty C, Collins JA, Bijlsma EK, Richards F, et al. CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J Med Genet. 2013;50:696\u2013703.","journal-title":"J Med Genet"},{"key":"1546_CR3","doi-asserted-by":"publisher","unstructured":"Apolin\u00e1rio TA, Paiva CLA, Agostinho LA. REVIEW-ARTICLE Intermediate alleles of Huntington\u2019s disease HTT gene in different populations worldwide: a systematic review. Genet Mol Res. 2017;16. https:\/\/doi.org\/10.4238\/gmr16029648.","DOI":"10.4238\/gmr16029648"},{"key":"1546_CR4","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1002\/mds.21195","volume":"22","author":"C Kenney","year":"2007","unstructured":"Kenney C, Powell S, Jankovic J. Autopsy-proven Huntington\u2019s disease with 29 trinucleotide repeats. Mov Disord. 2007;22:127\u201330.","journal-title":"Mov Disord"},{"key":"1546_CR5","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1212\/WNL.0b013e318294b304","volume":"80","author":"A Killoran","year":"2013","unstructured":"Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, et al. Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Neurology. 2013;80:2022\u20137. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23624566.","journal-title":"Neurology"},{"key":"1546_CR6","doi-asserted-by":"publisher","unstructured":"Cubo E, Ramos-Arroyo MA, Martinez-Horta S, Mart\u00ednez-Descalls A, Calvo S, Gil-Polo C. Clinical manifestations of intermediate allele carriers in Huntington disease. Neurology. 2016. https:\/\/doi.org\/10.1212\/WNL.0000000000002944; https:\/\/www.neurology.org\/lookup\/doi\/10.1212\/WNL.0000000000002944.","DOI":"10.1212\/WNL.0000000000002944"},{"key":"1546_CR7","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.jns.2019.05.010","volume":"402","author":"D Savitt","year":"2019","unstructured":"Savitt D, Jankovic J. Clinical phenotype in carriers of intermediate alleles in the huntingtin gene. J Neurol Sci. 2019;402:57\u201361.","journal-title":"J Neurol Sci"},{"key":"1546_CR8","doi-asserted-by":"crossref","unstructured":"Jevtic SD, Provias JP. Case report and literature review of Huntington disease with intermediate CAG expansion. BMJ Neurol Open. 2020;2:e000027.","DOI":"10.1136\/bmjno-2019-000027"},{"key":"1546_CR9","doi-asserted-by":"publisher","first-page":"117452","DOI":"10.1016\/j.jns.2021.117452","volume":"425","author":"A Reguera Acu\u00f1a","year":"2021","unstructured":"Reguera Acu\u00f1a A, Su\u00e1rez San Mart\u00edn E, Garc\u00eda Fern\u00e1ndez C, Fern\u00e1ndez Men\u00e9ndez S, Bl\u00e1zquez Estrada M, Amor\u00edn D\u00edaz M, et al. A series of cases with Huntington-like phenotype and intermediate repeats in HTT. J Neurol Sci. 2021;425:117452. https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022510X21001465.","journal-title":"J Neurol Sci"},{"key":"1546_CR10","doi-asserted-by":"publisher","first-page":"215.e9","DOI":"10.1016\/j.neurobiolaging.2018.11.014","volume":"76","author":"M Men\u00e9ndez-Gonz\u00e1lez","year":"2019","unstructured":"Men\u00e9ndez-Gonz\u00e1lez M, Clarim\u00f3n J, Rosas-Allende I, Bl\u00e1zquez M, San Mart\u00edn ES, Garc\u00eda-Fern\u00e1ndez C, et al. HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer\u2019s disease. Neurobiol Aging. 2019;76:215.e9\u2013e14.","journal-title":"Neurobiol Aging"},{"key":"1546_CR11","doi-asserted-by":"publisher","first-page":"139.e1","DOI":"10.1016\/j.neurobiolaging.2019.10.017","volume":"87","author":"I Rosas","year":"2020","unstructured":"Rosas I, Mart\u00ednez C, Clarim\u00f3n J, Lle\u00f3 A, Ill\u00e1n-Gala I, Dols-Icardo O, et al. Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer\u2019s disease. Neurobiol Aging. 2020;87:139.e1\u20137. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31810584.","journal-title":"Neurobiol Aging"},{"key":"1546_CR12","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1002\/mds.29153","volume":"37","author":"S P\u00e9rez-Oliveira","year":"2022","unstructured":"P\u00e9rez-Oliveira S, \u00c1lvarez I, Rosas I, Menendez-Gonz\u00e1lez M, Bl\u00e1zquez-Estrada M, Aguilar M, et al. Intermediate and expanded HTT alleles and the risk for \u03b1-synucleinopathies. Mov Disord. 2022;37:1841\u20139.","journal-title":"Mov Disord"},{"key":"1546_CR13","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/ng0893-387","volume":"4","author":"M Duyao","year":"1993","unstructured":"Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, et al. Trinucleotide repeat length instability and age of onset in Huntington\u2019s disease. Nat Genet. 1993;4:387\u201392. http:\/\/www.nature.com\/articles\/ng0893-387.","journal-title":"Nat Genet"},{"key":"1546_CR14","doi-asserted-by":"crossref","unstructured":"Gusella JF, Macdonald ME, Lee JM. Genetic modifiers of Huntington\u2019s disease. Mov Disord. 2014;29:1359\u201365.","DOI":"10.1002\/mds.26001"},{"key":"1546_CR15","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.cell.2019.06.036","volume":"178","author":"Genetic Modifiers of Huntington\u2019s D","year":"2019","unstructured":"Genetic Modifiers of Huntington\u2019s Disease (GeM-HD) Consortium. CAG repeat not polyglutamine length determines timing of Huntington\u2019s disease onset. Cell. 2019;178:887\u2013900.e14. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31398342.","journal-title":"Cell"},{"key":"1546_CR16","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, Maxwell A, Cumming SA, Hensman Moss DJ, Alshammari AM, Flower MD, 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. 2019;48:568\u201380. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31607598.","journal-title":"EBioMedicine"},{"key":"1546_CR17","doi-asserted-by":"crossref","unstructured":"Hong EP, MacDonald ME, Wheeler VC, Jones L, Holmans P, Orth M, et al. Huntington\u2019s disease pathogenesis: two sequential components. J Huntingtons Dis. 2021;10:35\u201351.","DOI":"10.3233\/JHD-200427"},{"key":"1546_CR18","doi-asserted-by":"publisher","first-page":"e64674","DOI":"10.7554\/eLife.64674","volume":"10","author":"R Kacher","year":"2021","unstructured":"Kacher R, Lejeune FX, No\u00ebl S, Cazeneuve C, Brice A, Humbert S, et al. Propensity for somatic expansion increases over the course of life in huntington disease. Elife. 2021;10:e64674.","journal-title":"Elife"},{"key":"1546_CR19","doi-asserted-by":"publisher","first-page":"3039","DOI":"10.1093\/hmg\/ddp242","volume":"18","author":"M Swami","year":"2009","unstructured":"Swami M, Hendricks AE, Gillis T, Massood T, Mysore J, Myers RH, 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. 2009;18:3039\u201347.","journal-title":"Hum Mol Genet"},{"key":"1546_CR20","doi-asserted-by":"crossref","unstructured":"Donaldson J, Powell S, Rickards N, Holmans P, Jones L. What is the pathogenic CAG expansion length in Huntington\u2019s disease?. J Huntingtons Dis. 2021;10:175\u2013202. https:\/\/www.medra.org\/servlet\/aliasResolver?alias=iospress&doi=10.3233\/JHD-200445.","DOI":"10.3233\/JHD-200445"},{"key":"1546_CR21","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1093\/hmg\/ddac224","volume":"32","author":"A Ruiz de Sabando","year":"2023","unstructured":"Ruiz de Sabando A, Urrutia Lafuente E, Galbete A, Ciosi M, Garc\u00eda Amigot F, Garc\u00eda Solaesa V, et al. Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease. Hum Mol Genet. 2023;32:897\u2013906. https:\/\/academic.oup.com\/hmg\/article\/32\/6\/897\/6708359.","journal-title":"Hum Mol Genet"},{"key":"1546_CR22","doi-asserted-by":"crossref","unstructured":"Ciosi M, Cumming SA, Alshammari AM, Symeonidi E, Herzyk P, McGuinness D, 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. Protoc Exch. 2018. https:\/\/protocolexchange.researchsquare.com\/article\/nprot-6621\/v2.","DOI":"10.1038\/protex.2018.089"},{"key":"1546_CR23","unstructured":"Gomes-Pereira M, Bidichandani SI, Monckton DG. Analysis of unstable triplet repeats using small-pool polymerase chain reaction. In: Trinucleotide repeat protocols. Methods Mol Biol. 2004;277:61\u201376. http:\/\/link.springer.com\/10.1385\/1-59259-804-8:061."},{"key":"1546_CR24","doi-asserted-by":"publisher","first-page":"e235","DOI":"10.1371\/journal.pcbi.0030235","volume":"3","author":"S Kaplan","year":"2007","unstructured":"Kaplan S, Itzkovitz S, Shapiro E. A universal mechanism ties genotype to phenotype in trinucleotide diseases. PLoS Comput Biol. 2007;3:e235.","journal-title":"PLoS Comput Biol"},{"key":"1546_CR25","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.1093\/hmg\/ddg352","volume":"12","author":"L Kennedy","year":"2003","unstructured":"Kennedy L, Evans E, Chen CM, Craven L, Detloff PJ, Ennis M, et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet. 2003;12:3359\u201367.","journal-title":"Hum Mol Genet"},{"key":"1546_CR26","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1093\/hmg\/2.9.1397","volume":"2","author":"M Anvret","year":"1993","unstructured":"Anvret M, Ahlberg G, Grandell U, Hedberg B, Johnson K, Edstr\u014dm L. Larger expansions of the CTG repeat in muscle compared to lymphocytes from patients with myotonic dystrophy. Hum Mol Genet. 1993;2:1397\u2013400. https:\/\/academic.oup.com\/hmg\/article-lookup\/doi\/10.1093\/hmg\/2.9.1397.","journal-title":"Hum Mol Genet"},{"key":"1546_CR27","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1002\/mds.28086","volume":"35","author":"DA Hall","year":"2020","unstructured":"Hall DA, Nag S, Ouyang B, Bennett DA, Liu Y, Ali A, et al. Fragile X gray zone alleles are associated with signs of Parkinsonism and earlier death. Mov Disord. 2020;35:1448\u201356.","journal-title":"Mov Disord"},{"key":"1546_CR28","doi-asserted-by":"publisher","first-page":"157.e1","DOI":"10.1016\/j.neurobiolaging.2017.11.011","volume":"64","author":"S Lattante","year":"2018","unstructured":"Lattante S, Pomponi MG, Conte A, Marangi G, Bisogni G, Patanella AK, et al. ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis. Neurobiol Aging. 2018;64:157.e1\u20135.","journal-title":"Neurobiol Aging"},{"key":"1546_CR29","doi-asserted-by":"publisher","first-page":"2671","DOI":"10.1093\/brain\/awac167","volume":"145","author":"JD Glass","year":"2022","unstructured":"Glass JD, Dewan R, Ding J, Gibbs JR, Dalgard C, Keagle PJ, et al. ATXN2 intermediate expansions in amyotrophic lateral sclerosis. Brain. 2022;145:2671\u20136. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/35521889.","journal-title":"Brain"},{"key":"1546_CR30","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1212\/WNL.0b013e31827f08ea","volume":"80","author":"E G\u00f3mez-Tortosa","year":"2013","unstructured":"G\u00f3mez-Tortosa E, Gallego J, Guerrero-L\u00f3pez R, Marcos A, Gil-Neciga E, Sainz MJ, et al. C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration. Neurology. 2013;80:366\u201370.","journal-title":"Neurology"},{"key":"1546_CR31","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s40478-019-0724-4","volume":"7","author":"A Iacoangeli","year":"2019","unstructured":"Iacoangeli A, Al Khleifat A, Jones AR, Sproviero W, Shatunov A, Opie-Martin S, et al. C9orf72 intermediate expansions of 24-30 repeats are associated with ALS. Acta Neuropathol Commun. 2019;7:115.","journal-title":"Acta Neuropathol Commun"},{"key":"1546_CR32","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1002\/ajmg.b.32193","volume":"162","author":"A Semaka","year":"2013","unstructured":"Semaka A, Kay C, Doty CN, Collins JA, Tam N, Hayden MR. High frequency of intermediate alleles on huntington disease-associated haplotypes in British Columbia\u2019s general population. Am J Med Genet Part B Neuropsychiatr Genet. 2013;162:864\u201371. https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.b.32193.","journal-title":"Am J Med Genet Part B Neuropsychiatr Genet"},{"key":"1546_CR33","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1002\/mds.21958","volume":"23","author":"J Andrich","year":"2008","unstructured":"Andrich J, Arning L, Wieczorek S, Kraus PH, Gold R, Saft C. Huntington\u2019s disease as caused by 34 CAG repeats. Mov Disord. 2008;23:879\u201381.","journal-title":"Mov Disord"},{"key":"1546_CR34","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.jns.2008.11.005","volume":"277","author":"YO Herishanu","year":"2009","unstructured":"Herishanu YO, Parvari R, Pollack Y, Shelef I, Marom B, Martino T, et al. Huntington disease in subjects from an Israeli Karaite community carrying alleles of intermediate and expanded CAG repeats in the HTT gene: Huntington disease or phenocopy? J Neurol Sci. 2009;277:143\u20136.","journal-title":"J Neurol Sci"},{"key":"1546_CR35","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1136\/jnnp.2008.170902","volume":"81","author":"JL Groen","year":"2010","unstructured":"Groen JL, De Bie RM, Foncke EMJ, Roos RAC, Leenders KL, Tijssen MAJ. Late-onset Huntington disease with intermediate CAG repeats: true or false? J Neurol Neurosurg Psychiatry. 2010;81:228\u201330.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"1546_CR36","doi-asserted-by":"publisher","first-page":"116","DOI":"10.3810\/pgm.2011.09.2466","volume":"123","author":"AD Ha","year":"2011","unstructured":"Ha AD, Jankovic J. Exploring the correlates of intermediate CAG repeats in Huntington disease. Postgrad Med. 2011;123:116\u201321.","journal-title":"Postgrad Med"},{"key":"1546_CR37","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1002\/mds.23623","volume":"26","author":"F Squitieri","year":"2011","unstructured":"Squitieri F, Esmaeilzadeh M, Ciarmiello A, Jankovic J. Caudate glucose hypometabolism in a subject carrying an unstable allele of intermediate CAG(33) repeat length in the Huntington\u2019s disease gene. Mov Disord. 2011;26:925\u20137. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21370274.","journal-title":"Mov Disord"},{"key":"1546_CR38","doi-asserted-by":"publisher","first-page":"e85","DOI":"10.1176\/appi.neuropsych.13110347","volume":"27","author":"B Ziso","year":"2015","unstructured":"Ziso B, Larner AJ, Alusi SH. Stuck in the middle: Huntington\u2019s disease or not Huntington\u2019s disease?. J Neuropsychiatry Clin Neurosci. 2015;27:e85\u20136. http:\/\/psychiatryonline.org\/doi\/abs\/10.1176\/appi.neuropsych.13110347.","journal-title":"J Neuropsychiatry Clin Neurosci"},{"key":"1546_CR39","doi-asserted-by":"crossref","unstructured":"Garcia-Ruiz PJ, Garcia-Caldentey J, Feliz C, Del Val J, Herranz A, Mart\u00ednez-Castrillo JC. Late onset Huntington\u2019s disease with 29 CAG repeat expansion. J Neurol Sci. 2016;363:114\u20135.","DOI":"10.1016\/j.jns.2016.02.030"},{"key":"1546_CR40","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3390\/brainsci9100245","volume":"9","author":"S Jot","year":"2019","unstructured":"Jot S. Parkinsonism with a hint of huntington\u2019s from 29 cag repeats in HTT. Brain Sci. 2019;9:245.","journal-title":"Brain Sci"},{"key":"1546_CR41","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.ajhg.2019.04.007","volume":"104","author":"GEB Wright","year":"2019","unstructured":"Wright GEB, Collins JA, Kay C, McDonald C, Dolzhenko E, Xia Q, et al. Length of uninterrupted CAG, independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington disease. Am J Hum Genet. 2019;104:1116\u201326.","journal-title":"Am J Hum Genet"},{"key":"1546_CR42","doi-asserted-by":"publisher","first-page":"e1005267","DOI":"10.1371\/journal.pgen.1005267","volume":"11","author":"H Budworth","year":"2015","unstructured":"Budworth H, Harris FR, Williams P, Lee DY, Holt A, Pahnke J, et al. Suppression of somatic expansion delays the onset of pathophysiology in a mouse model of Huntington\u2019s disease. PLoS Genet. 2015;11:e1005267.","journal-title":"PLoS Genet"},{"key":"1546_CR43","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/ng0795-344","volume":"10","author":"SS Chong","year":"1995","unstructured":"Chong SS, McCall AE, Cota J, Subramony SH, Orr HT, Hughes MR, et al. Gametic and somatic tissue\u2013specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1995;10:344\u201350.","journal-title":"Nat Genet"},{"key":"1546_CR44","unstructured":"M\u00e4tlik K, Baffuto M, Kus L, Davis DA, Paul MR, Carroll TS, et al. Cell type specific CAG repeat expansion and toxicity of mutant huntingtin in human striatal and cerebellar cell types. bioRxiv. 2023. http:\/\/biorxiv.org\/content\/early\/2023\/04\/24\/2023.04.24.538082.abstract."},{"key":"1546_CR45","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1093\/hmg\/ddm054","volume":"16","author":"PF Shelbourne","year":"2007","unstructured":"Shelbourne PF, Keller-McGandy C, Bi WL, Yoon SR, Dubeau L, Veitch NJ, et al. Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Hum Mol Genet. 2007;16:1133\u201342.","journal-title":"Hum Mol Genet"},{"key":"1546_CR46","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.neuron.2020.11.005","volume":"109","author":"R Dewan","year":"2021","unstructured":"Dewan R, Chia R, Ding J, Hickman RA, Stein TD, Abramzon Y, et al. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 2021;109:448\u201360.e4.","journal-title":"Neuron"},{"key":"1546_CR47","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1016\/j.neuron.2021.04.010","volume":"109","author":"Q Thomas","year":"2021","unstructured":"Thomas Q, Coarelli G, Heinzmann A, Le Ber I, Amador M, del M, et al. Questioning the causality of HTT CAG-repeat expansions in FTD\/ALS. Neuron. 2021;109:1945\u20136. https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0896627321002609.","journal-title":"Neuron"},{"key":"1546_CR48","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1136\/jnnp.2004.036806","volume":"76","author":"MA Ramos-Arroyo","year":"2005","unstructured":"Ramos-Arroyo MA. Incidence and mutation rates of Huntington\u2019s disease in Spain: experience of 9 years of direct genetic testing. J Neurol Neurosurg Psychiatry. 2005;76:337\u201342.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"1546_CR49","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.3390\/brainsci11121621","volume":"11","author":"J Achenbach","year":"2021","unstructured":"Achenbach J, Saft C. Another perspective on Huntington\u2019s disease: disease burden in family members and pre-manifest HD when compared to genotype-negative participants from ENROLL-HD. Brain Sci. 2021;11:1621.","journal-title":"Brain Sci"},{"key":"1546_CR50","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.1399-0004.2004.00241.x","volume":"65","author":"D Langbehn","year":"2004","unstructured":"Langbehn D, Brinkman R, Falush D, Paulsen J, Hayden M. A new model for prediction of the age of onset and penetrance for Huntington\u2019s disease based on CAG length. Clin Genet. 2004;65:267\u201377. https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1399-0004.2004.00241.x.","journal-title":"Clin Genet"}],"container-title":["European Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01546-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01546-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01546-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T16:44:07Z","timestamp":1719938647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01546-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,4]]},"references-count":50,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["1546"],"URL":"https:\/\/doi.org\/10.1038\/s41431-024-01546-6","relation":{},"ISSN":["1018-4813","1476-5438"],"issn-type":[{"value":"1018-4813","type":"print"},{"value":"1476-5438","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,4]]},"assertion":[{"value":"16 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 January 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Within the last 5 years, DGM has been a scientific consultant and\/or received an honoraria\/stock options\/grants from AMO Pharma, Charles River, LoQus23, Triplet Therapeutics, Ono Pharmaceuticals, Rgenta Therapeutics, Novartis, Dyne and Vertex Pharmaceuticals. DGM also had research contracts with AMO Pharma and Vertex Pharmaceuticals.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was carried out according to the Spanish Biomedical Research Law (Ley 14\/2007, de 3 de julio, de Investigaci\u00f3n Biom\u00e9dica)\n                      \n                      . Participation in the study was approved by all collaborative centres. The study was approved by the Central Ethics Committee of Clinical Research \u201cComit\u00e9 de \u00c9tica de la Investigaci\u00f3n con medicamentos (CEIm)\u201d of Gobierno de Navarra (PI_2015\/78. Res. 662, 18th October 2019). Written informed consent was obtained from all participants required by the CEIm, and data were deidentified. For individuals of the three HD families studied a specific written consent was signed and archived.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}