{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:14:32Z","timestamp":1785208472719,"version":"3.55.0"},"reference-count":14,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The Research Committee of Ataxia, Health Labor Sciences Research Grant, Ministry of Health, Labor, and Welfare"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hum Genet"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Spinocerebellar degeneration (SCD) is a clinically and genetically diverse group, and the dominant form of SCD (AD-SCD) is generally referred to as spinocerebellar ataxia (SCA) that primarily affects the cerebellum. Some patients do not have a definitive genetic diagnosis but may carry unknown variants of known causative genes. Here, we screened for known SCA-associated genes in patients with suspected SCA. We examined 174 patients with SCA lacking abnormal repeat expansion of known causative genes. Whole-exome sequencing (WES) was performed to screen for variants in SCA-associated genes. The identified variants were confirmed by Sanger sequencing, and their pathogenicity was determined using five web-based algorithms. WES revealed novel single-nucleotide variants (SNVs) in three genes,\n                    <jats:italic>ELOVL4<\/jats:italic>\n                    ,\n                    <jats:italic>ELOVL5<\/jats:italic>\n                    , and\n                    <jats:italic>GRM1<\/jats:italic>\n                    . Patients presented with symptoms other than cerebellar symptoms. One patient with an\n                    <jats:italic>ELOVL4<\/jats:italic>\n                    variant exhibited skin changes, a typical symptom of\n                    <jats:italic>ELOVL4<\/jats:italic>\n                    SCA, whereas the other\n                    <jats:italic>ELOVL4<\/jats:italic>\n                    SCA patient had no skin changes and exhibited mild parkinsonism and calcification in the globus pallidus and dentate nucleus. The patient with an\n                    <jats:italic>ELOVL5<\/jats:italic>\n                    variant exhibited bladder and rectal disturbances. Finally, patients with\n                    <jats:italic>GRM1<\/jats:italic>\n                    variants showed few common features beyond the cerebellar symptoms. One patient showed white matter lesions, cognitive decline, and no-no head tremors, whereas the other showed spasticity. The identification of novel SNVs in these known SCA-associated genes will expand our understanding of the genetic landscape of SCA and facilitate the diagnosis of previously undiagnosed patients.\n                  <\/jats:p>","DOI":"10.1038\/s10038-025-01405-2","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T07:58:03Z","timestamp":1757663883000},"page":"35-39","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Whole exome sequencing in Japanese spinocerebellar ataxia identifies novel variants"],"prefix":"10.1038","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1364-7239","authenticated-orcid":false,"given":"Tomoaki","family":"Watanabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9266-2543","authenticated-orcid":false,"given":"Kodai","family":"Kume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5206-5979","authenticated-orcid":false,"given":"Takashi","family":"Kurashige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Ohshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Tazuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misako","family":"Kaido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Maetani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-8717","authenticated-orcid":false,"given":"Hirofumi","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1405-0901","authenticated-orcid":false,"given":"Hideshi","family":"Kawakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"1405_CR1","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1007\/s00415-018-9076-4","volume":"266","author":"R Sullivan","year":"2019","unstructured":"Sullivan R, Yau WY, O\u2019Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol. 2019;266:533\u201344.","journal-title":"J Neurol"},{"key":"1405_CR2","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1002\/humu.23946","volume":"41","author":"KJ Ngo","year":"2020","unstructured":"Ngo KJ, Rexach JE, Lee H, Petty LE, Perlman S, Valera JM, et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Hum Mutat. 2020;41:487\u2013501.","journal-title":"Hum Mutat"},{"key":"1405_CR3","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.parkreldis.2020.08.040","volume":"80","author":"M Kim","year":"2020","unstructured":"Kim M, Kim AR, Kim JS, Park J, Youn J, Ahn JH, et al. Clarification of undiagnosed ataxia using whole-exome sequencing with clinical implications. Parkinsonism Relat Disord. 2020;80:58\u201364.","journal-title":"Parkinsonism Relat Disord"},{"key":"1405_CR4","doi-asserted-by":"publisher","first-page":"2860","DOI":"10.1093\/brain\/awx251","volume":"140","author":"EAR Nibbeling","year":"2017","unstructured":"Nibbeling EAR, Duarri A, Verschuuren-Bemelmans CC, Fokkens MR, Karjalainen JM, Smeets C, et al. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain. 2017;140:2860\u201378.","journal-title":"Brain"},{"key":"1405_CR5","doi-asserted-by":"publisher","first-page":"e1010625","DOI":"10.1371\/journal.pgen.1010625","volume":"19","author":"Y Kawai","year":"2023","unstructured":"Kawai Y, Watanabe Y, Omae Y, Miyahara R, Khor SS, Noiri E, et al. Exploring the genetic diversity of the Japanese population: insights from a large-scale whole genome sequencing analysis. PLoS Genet. 2023;19:e1010625.","journal-title":"PLoS Genet"},{"key":"1405_CR6","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1001\/archderm.1972.01620110019005","volume":"106","author":"JM Giroux","year":"1972","unstructured":"Giroux JM, Barbeau A. Erythrokeratodermia with ataxia. Arch Dermatol. 1972;106:183\u20138.","journal-title":"Arch Dermatol"},{"key":"1405_CR7","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1001\/jamaneurol.2013.6337","volume":"71","author":"M Cadieux-Dion","year":"2014","unstructured":"Cadieux-Dion M, Turcotte-Gauthier M, Noreau A, Martin C, Meloche C, Gravel M, et al. Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol. 2014;71:470\u20135.","journal-title":"JAMA Neurol"},{"key":"1405_CR8","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1001\/jamaneurol.2015.0610","volume":"72","author":"K Ozaki","year":"2015","unstructured":"Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y, Majima T, et al. A novel mutation in ELOVL4 leading to spinocerebellar ataxia (SCA) with the hot cross bun sign but lacking erythrokeratodermia: a broadened spectrum of SCA34. JAMA Neurol. 2015;72:797\u2013805.","journal-title":"JAMA Neurol"},{"key":"1405_CR9","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/mdc3.13550","volume":"9","author":"AK Naidoo","year":"2022","unstructured":"Naidoo AK, Wells CD, Rugbeer Y, Naidoo N. The \u201cHot Cross Bun Sign\u201d in spinocerebellar ataxia types 2 and 7-case reports and review of literature. Mov Disord Clin Pract. 2022;9:1105\u201313.","journal-title":"Mov Disord Clin Pract"},{"key":"1405_CR10","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405\u201324.","journal-title":"Genet Med"},{"key":"1405_CR11","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.ajhg.2014.07.001","volume":"95","author":"E Di Gregorio","year":"2014","unstructured":"Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N, et al. ELOVL5 mutations cause spinocerebellar ataxia 38. 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Brain. 2017;140:1579\u201394.","journal-title":"Brain"},{"key":"1405_CR14","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1136\/jnnp-2016-314863","volume":"88","author":"M Hadjivassiliou","year":"2017","unstructured":"Hadjivassiliou M, Martindale J, Shanmugarajah P, Gr\u00fcnewald RA, Sarrigiannis PG, Beauchamp N, et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry. 2017;88:301\u201309.","journal-title":"J Neurol Neurosurg Psychiatry"}],"container-title":["Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s10038-025-01405-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s10038-025-01405-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s10038-025-01405-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T23:05:21Z","timestamp":1767654321000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s10038-025-01405-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":14,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["1405"],"URL":"https:\/\/doi.org\/10.1038\/s10038-025-01405-2","relation":{},"ISSN":["1434-5161","1435-232X"],"issn-type":[{"value":"1434-5161","type":"print"},{"value":"1435-232X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,12]]},"assertion":[{"value":"27 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 September 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}