{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:06:03Z","timestamp":1792667163902,"version":"4.5.0"},"reference-count":16,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2021-1061 and RF 193021X0029"],"award-info":[{"award-number":["075-15-2021-1061 and RF 193021X0029"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann\u2013Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann\u2013Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T&gt;C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G&gt;A and c.3337-11T&gt;C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T&gt;C variant. Furthermore, our investigation led to the reclassification of the c.3677T&gt;C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann\u2013Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders.<\/jats:p>","DOI":"10.3390\/genes15020180","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T08:11:27Z","timestamp":1706515887000},"page":"180","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Genetic Basis of the First Patient with Wiedemann\u2013Rautenstrauch Syndrome in the Russian Federation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8728-8574","authenticated-orcid":false,"given":"Valeriia A.","family":"Kovalskaia","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia L.","family":"Kungurtseva","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Department, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima M.","family":"Bostanova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8249-343X","authenticated-orcid":false,"given":"Peter A.","family":"Vasiliev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyacheslav Y.","family":"Tabakov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariia D.","family":"Orlova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna S.","family":"Povolotskaya","sequence":"additional","affiliation":[{"name":"JSC \u201cFirst Genetics Laboratory\u201d, 111123 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4392-6714","authenticated-orcid":false,"given":"Olga G.","family":"Novoselova","sequence":"additional","affiliation":[{"name":"JSC \u201cFirst Genetics Laboratory\u201d, 111123 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman A.","family":"Bikanov","sequence":"additional","affiliation":[{"name":"JSC \u201cFirst Genetics Laboratory\u201d, 111123 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariia A.","family":"Akhyamova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia V.","family":"Tikhonovich","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Department, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia V.","family":"Popovich","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Department, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa V.","family":"Vitebskaya","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Department, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena L.","family":"Dadali","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1285-9093","authenticated-orcid":false,"given":"Oxana P.","family":"Ryzhkova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1007\/s00415-019-09574-9","article-title":"POLR3A-related spastic ataxia: New mutations and a look into the phenotype","volume":"267","author":"Infante","year":"2020","journal-title":"J. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1136\/jmedgenet-2012-101357","article-title":"Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and\/or hypogonadotropic hypogonadism","volume":"50","author":"Daoud","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.ajhg.2018.10.010","article-title":"Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome","volume":"103","author":"Wambach","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","unstructured":"(2023, November 26). Available online: https:\/\/www.orpha.net\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1002\/ajmg.a.37960","article-title":"Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A","volume":"170","author":"Jay","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1136\/jmedgenet-2018-105528","article-title":"Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome","volume":"55","author":"Paolacci","year":"2018","journal-title":"J. Med. 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Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ajhg.2011.07.014","article-title":"Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy","volume":"89","author":"Bernard","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1093\/brain\/awx291","article-title":"Reply: POLR3A variants in hereditary spastic paraplegia and ataxia","volume":"141","author":"Minnerop","year":"2018","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1007\/s10072-021-05462-1","article-title":"POLR3A variants in hereditary spastic paraparesis and ataxia: Clinical, genetic, and neuroradiological findings in a cohort of Italian patients","volume":"43","author":"Gallo","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1212\/WNL.0000000000002612","article-title":"Diffuse hypomyelination is not obligate for POLR3-related disorders","volume":"86","author":"Cayami","year":"2016","journal-title":"Neurology"},{"key":"ref_15","unstructured":"(2024, January 15). Available online: https:\/\/gnomad.broadinstitute.org\/variant\/10-78009515-C-T?dataset=gnomad_r4."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1093\/brain\/awx095","article-title":"Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia","volume":"140","author":"Minnerop","year":"2017","journal-title":"Brain"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/2\/180\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:51:07Z","timestamp":1760104267000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/2\/180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,29]]},"references-count":16,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["genes15020180"],"URL":"https:\/\/doi.org\/10.3390\/genes15020180","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,29]]}}}