{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:26:20Z","timestamp":1788402380994,"version":"build-2803163510"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Gordon Holmes syndrome (GHS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Mutations in the Ring Finger Protein 216 (\n                      <jats:italic>RNF216<\/jats:italic>\n                      ) gene have been known to be associated with GHS therewithal\n                      <jats:italic>RNF216<\/jats:italic>\n                      mutations have been detected in cases with Huntington-like disease, 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      Here we report a novel homozygous frameshift mutation in\n                      <jats:italic>RNF216<\/jats:italic>\n                      gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, and cognitive decline diagnosed with GHS also co-occurrence of parkinsonism and dystonia which was not reported before.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We report an extremely rare case of GHS. The core features of GHS are well defined, but genotype\u2013phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined. Further studies should explain the factors of phenotypic variability present in GHS patients with\n                      <jats:italic>RNF216<\/jats:italic>\n                      mutations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12920-023-01529-4","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T03:31:40Z","timestamp":1683689500000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome"],"prefix":"10.1186","volume":"16","author":[{"given":"Nazl\u0131","family":"Durmaz \u00c7elik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebru","family":"Erzurumluo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serkan","family":"\u00d6zben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U\u011fur","family":"Toprak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6knur","family":"Yorulmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sevilhan","family":"Artan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serhat","family":"\u00d6zkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"issue":"4","key":"1529_CR1","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1093\/brain\/30.4.466","volume":"30","author":"G Holmes","year":"1908","unstructured":"Holmes G. A form of familial degeneration of the cerebellum. Brain. 1908;30(4):466\u201389.","journal-title":"Brain"},{"issue":"7","key":"1529_CR2","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1002\/mdc3.13308","volume":"8","author":"P Gonzalez-Latapi","year":"2021","unstructured":"Gonzalez-Latapi P, Sousa M, Lang AE. Movement disorders associated with hypogonadism. Movement Disord Clin Pract. 2021;8(7):997\u20131011.","journal-title":"Movement Disord Clin Pract"},{"issue":"2","key":"1529_CR3","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1111\/acel.12551","volume":"16","author":"N Husain","year":"2017","unstructured":"Husain N, Yuan Q, Yen YC, Pletnikova O, Sally DQ, Worley P, et al. TRIAD3\/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation. Aging Cell. 2017;16(2):281\u201392.","journal-title":"Aging Cell"},{"key":"1529_CR4","doi-asserted-by":"publisher","first-page":"793547","DOI":"10.3389\/fneur.2021.793547","volume":"12","author":"L Nanetti","year":"2022","unstructured":"Nanetti L, Di Bella D, Magri S, Fichera M, Sarto E, Castaldo A, et al. Multifaceted and age-dependent phenotypes associated with biallelic PNPLA6 gene variants: eight novel cases and review of the literature. Front Neurol. 2022;12:793547.","journal-title":"Front Neurol"},{"issue":"3","key":"1529_CR5","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1002\/mdc3.12721","volume":"6","author":"CR Calandra","year":"2019","unstructured":"Calandra CR, Mocarbel Y, Vishnopolska SA, Toneguzzo V, Oliveri J, Cazado EC, et al. Gordon Holmes Syndrome caused by RNF216 novel mutation in 2 Argentinean siblings. Movement Disord Clin Pract. 2019;6(3):259.","journal-title":"Movement Disord Clin Pract"},{"issue":"5","key":"1529_CR6","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1002\/acn3.51047","volume":"7","author":"KL Chen","year":"2020","unstructured":"Chen KL, Zhao GX, Wang H, Wei L, Huang YY, Chen SD, et al. A novel de novo RNF216 mutation associated with autosomal recessive Huntington-like disorder. Ann Clin Trans Neurol. 2020;7(5):860\u20134.","journal-title":"Ann Clin Trans Neurol"},{"key":"1529_CR7","doi-asserted-by":"publisher","first-page":"626","DOI":"10.3389\/fendo.2020.00626","volume":"11","author":"V Neocleous","year":"2020","unstructured":"Neocleous V, Fanis P, Toumba M, Tanteles GA, Schiza M, Cinarli F, et al. GnRH deficient patients with congenital hypogonadotropic hypogonadism: novel genetic findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A genes in a case series and review of the literature. Front Endocrinol. 2020;11:626.","journal-title":"Front Endocrinol"},{"issue":"5","key":"1529_CR8","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(5):405\u201323.","journal-title":"Genet Med"},{"issue":"21","key":"1529_CR9","doi-asserted-by":"publisher","first-page":"1992","DOI":"10.1056\/NEJMoa1215993","volume":"368","author":"DH Margolin","year":"2013","unstructured":"Margolin DH, Kousi M, Chan Y-M, Lim ET, Schmahmann JD, Hadjivassiliou M, et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. 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Pract Neurol. 2017;17(6):476\u20138.","journal-title":"Pract Neurol"},{"issue":"9","key":"1529_CR13","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1016\/j.parkreldis.2015.07.012","volume":"21","author":"C Ganos","year":"2015","unstructured":"Ganos C, Hersheson J, Adams M, Bhatia KP, Houlden H. The 4H syndrome due to RNF216 mutation. Parkinsonism Relat Disord. 2015;21(9):1122\u20133.","journal-title":"Parkinsonism Relat Disord"},{"issue":"8","key":"1529_CR14","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1002\/mdc3.12839","volume":"6","author":"M Lieto","year":"2019","unstructured":"Lieto M, Galatolo D, Roca A, Cocozza S, Pontillo G, Fico T, et al. Overt hypogonadism may not be a sentinel sign of RING finger protein 216: Two novel mutations associated with ataxia, chorea, and fertility. Movement Disord Clin Pract. 2019;6(8):724.","journal-title":"Movement Disord Clin Pract"},{"issue":"17","key":"1529_CR15","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1212\/WNL.0000000000001521","volume":"84","author":"P Santens","year":"2015","unstructured":"Santens P, Van Damme T, Steyaert W, Willaert A, Sablonni\u00e8re B, De Paepe A, et al. RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder. Neurology. 2015;84(17):1760\u20136.","journal-title":"Neurology"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-023-01529-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-023-01529-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-023-01529-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T03:47:30Z","timestamp":1683690450000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedgenomics.biomedcentral.com\/articles\/10.1186\/s12920-023-01529-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,9]]},"references-count":15,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["1529"],"URL":"https:\/\/doi.org\/10.1186\/s12920-023-01529-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-2416104\/v1","asserted-by":"object"}]},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,9]]},"assertion":[{"value":"26 December 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 May 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in studies involving human participant were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki decleration and its later amendments or comparable ethical standards. Written informed consent for publication of identifying images or other personal or clinical details was obtained from the patient.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication of identifying images or other personal or clinical details was obtained from the patient and participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing intrests for this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"98"}}