{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T21:43:22Z","timestamp":1771969402089,"version":"3.50.1"},"reference-count":16,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LE4223\/1\u20101"],"award-info":[{"award-number":["LE4223\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002287","name":"Progeria Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002287","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pathogenic biallelic variants in <jats:italic>POL3RA<\/jats:italic> have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent\u2010onset progressive spastic ataxia, as well as Wiedemann\u2013Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying <jats:italic>POLR3A<\/jats:italic> variants. Here we present the detailed clinical course of a 37\u2010year\u2010old woman in whom we identified a homozygous synonymous <jats:italic>POLR3A<\/jats:italic> variant c.3336G&gt;A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS\u2010like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported <jats:italic>POLR3A<\/jats:italic>\u2010associated disorders, mostly mimicking the WRS. Thus, our study expands the <jats:italic>POLR3A<\/jats:italic>\u2010mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic <jats:italic>POLR3A<\/jats:italic> variants.<\/jats:p>","DOI":"10.1002\/ajmg.a.62525","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T01:07:14Z","timestamp":1633655234000},"page":"216-223","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A novel homozygous synonymous variant further expands the phenotypic spectrum of <i><scp>POLR3A<\/scp>\u2010<\/i>related pathologies"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4496-244X","authenticated-orcid":false,"given":"Davor","family":"Lessel","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Rading","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan E.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Center for Gerontology and Healthcare Research Brown University  Providence Rhode Island USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Altm\u00fcller","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics University of Cologne  Cologne Germany"},{"name":"Berlin Institute of Health Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Core Facility Genomics  Berlin Germany"},{"name":"The Genomics unit Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC)  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie B.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics Hasbro Children's Hospital  Providence Rhode Island USA"},{"name":"Warren Alpert Medical School Brown University  Providence Rhode Island USA"},{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Kubisch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.07.014"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-016-0290-6"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15904"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37960"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3238\/arztebl.2019.0489"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-018-1957-1"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx095"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92280"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38246"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105528"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00477545"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.7.10.1006"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.10.010"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00441901"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001002"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.333989.119"}],"container-title":["American 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