{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:41:58Z","timestamp":1792204918993,"version":"4.4.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003425","name":"Department of Education, Government of Navarra","doi-asserted-by":"publisher","award":["0011-4809-2018-000001"],"award-info":[{"award-number":["0011-4809-2018-000001"]}],"id":[{"id":"10.13039\/501100003425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"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"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based controls (n\u2009=\u2009520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140 carriers of intermediate alleles. Clinical and family history data were obtained when available. Spanish normal alleles are enriched in C haplotypes (40.1%), whereas A1 (39.8%) and A2 (31.6%) prevail among intermediate and expanded alleles, respectively. Alleles\u2009\u2265\u200950 CAG repeats are primarily associated with haplotypes A2 (38.9%) and C (32%), which are also present in 50% and 21.4%, respectively, of HD families with large intergenerational expansions. Non-canonical variants of exon one sequence are less frequent, but much more diverse, in alleles of \u226527 CAG repeats. The deletion of CAACAG, one of the six rare variants not observed among smaller normal alleles, is associated with haplotype C and appears to correlate with larger intergenerational expansions and early onset of symptoms. Spanish HD haplotypes are characterized by a high genetic diversity, potentially admixed with other non-Caucasian populations, with a higher representation of A2 and C haplotypes than most European populations. Differences in haplotype distributions across the CAG length range support differential germline expansion dynamics, with A2 and C showing the largest intergenerational expansions. This haplotype-dependent germline instability may be driven by specific cis-elements, such as the CAACAG deletion.<\/jats:p>","DOI":"10.1093\/hmg\/ddac224","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T20:39:03Z","timestamp":1663792743000},"page":"897-906","source":"Crossref","is-referenced-by-count":11,"title":["Spanish<i>HTT<\/i>gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-465X","authenticated-orcid":false,"given":"Ainara","family":"Ruiz de Sabando","sequence":"first","affiliation":[{"name":"Hospital Universitario de Navarra, IdiSNA Department of Medical Genetics, , Pamplona 31008 , Spain"},{"name":"Universidad P\u00fablica de Navarra, IdiSNA Department of Health Sciences, , Pamplona 31008 , Spain"},{"name":"Fundaci\u00f3n Miguel Servet-Navarrabiomed, IdiSNA , Pamplona 31008 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0553-578X","authenticated-orcid":false,"given":"Edurne","family":"Urrutia Lafuente","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Miguel Servet-Navarrabiomed, IdiSNA , Pamplona 31008 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5622-5418","authenticated-orcid":false,"given":"Arkaitz","family":"Galbete","sequence":"additional","affiliation":[{"name":"Universidad P\u00fablica de Navarra, IdiSNA Department of Statistics, Informatics and Mathematics, , Pamplona 31006 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-4080","authenticated-orcid":false,"given":"Marc","family":"Ciosi","sequence":"additional","affiliation":[{"name":"University of Glasgow School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, , Glasgow G12 8QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0559-9131","authenticated-orcid":false,"given":"Ferm\u00edn","family":"Garc\u00eda Amigot","sequence":"additional","affiliation":[{"name":"Hospital Universitario de Navarra, IdiSNA Department of Medical Genetics, , Pamplona 31008 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5996-1429","authenticated-orcid":false,"given":"Virginia","family":"Garc\u00eda Solaesa","sequence":"additional","affiliation":[{"name":"Hospital Universitario de Navarra, IdiSNA Department of Medical Genetics, , Pamplona 31008 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Spanish HD Collaborative group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria \u00c1lvarez","family":"Mart\u00ednez","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 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