Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype

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dc.contributor.authorRuiz de Sabando, Ainara
dc.contributor.authorCiosi, Marc
dc.contributor.authorGalbete Jiménez, Arkaitz
dc.contributor.authorCumming, Sarah A.
dc.contributor.authorMonckton, Darren G.
dc.contributor.authorRamos Arroyo, María A.
dc.contributor.authorÁlvarez, Victoria
dc.contributor.authorMartínez-Descals, Asunción
dc.contributor.authorMila, Montserrat
dc.contributor.authorTrujillo-Tiebas, María José
dc.contributor.authorLópez-Sendón, José Luis
dc.contributor.authorFenollar-Cortés, María
dc.contributor.authorLegarda, Inés
dc.contributor.authorBernal Noguera, Sara
dc.contributor.authorMillán, J. M.
dc.contributor.authorDurán-Herrera, C.
dc.contributor.authorRuiz-Martínez, Javier
dc.contributor.authorRuiz Onandi, Rebeca
dc.contributor.departmentEstadística, Informática y Matemáticases_ES
dc.contributor.departmentEstatistika, Informatika eta Matematikaeu
dc.date.accessioned2024-09-12T15:46:40Z
dc.date.available2024-09-12T15:46:40Z
dc.date.issued2024
dc.date.updated2024-09-12T15:08:36Z
dc.description.abstractHuntington disease (HD) is a neurodegenerative disorder caused by ≥36 CAGs in the HTT gene. Intermediate alleles (IAs) (27–35 CAGs) are not considered HD-causing, but their potential association with neurocognitive symptoms remains controversial. As HTT 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 HTT 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 ± 18.6 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 HTT 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.en
dc.description.sponsorshipThis study was funded by the Instituto de Salud Carlos III (grant no. FIS PI15/02227), and the CHDI Foundation (Enroll-HD study). ARS was supported by a Fellowship of Departamento de Salud, Gobierno de Navarra (ref. 0011-4809-2018-000001).
dc.format.mimetypeapplication/pdfen
dc.identifier.citationRuiz de Sabando, A., Ciosi, M., Galbete, A., Cumming, S. A., Monckton, D. G., Ramos-Arroyo, M. A., Álvarez, V., Martinez-Descals, A., Mila, M., Trujillo-Tiebas, M. J., López-Sendón, J. L., Fenollar-Cortés, M., Legarda, I., Bernal Noguera, S., Millán, J. M., Durán-Herrera, C., Ruiz-Martínez, J., Ruiz Onandi, R. (2024) Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype. European Journal of Human Genetics, 1-9. https://doi.org/10.1038/s41431-024-01546-6.
dc.identifier.doi10.1038/s41431-024-01546-6
dc.identifier.issn1018-4813
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/51618
dc.language.isoeng
dc.publisherSpringer Nature
dc.relation.ispartofEuropean Journal of Human Genetics (2024), 32, 770 – 778
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//PI15%2F02227/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//0011-4809-2018-000001/
dc.relation.publisherversionhttps://doi.org/10.1038/s41431-024-01546-6
dc.rights© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHuntington diseaseen
dc.subjectIntermediate allelesen
dc.subjectSomatic CAG expansionen
dc.subjectGenotype-phenotype analysisen
dc.subjectNeurocognitive symptomsen
dc.subjectHTT geneen
dc.titleSomatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotypeen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication4bb570ab-10a2-4b9a-8ee8-893bbd090df6
relation.isAuthorOfPublication.latestForDiscovery4bb570ab-10a2-4b9a-8ee8-893bbd090df6

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