{"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":1771969402084,"version":"3.50.1"},"reference-count":20,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>POLR3A<\/jats:italic> encodes the largest subunit of the DNA\u2010dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non\u2010coding RNAs. <jats:italic>POLR3A<\/jats:italic>\u2010related disorders include variable phenotypes. The genotype\u2013phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46\u201355) had similar clinical features of early childhood\u2010onset hypodontia and adolescent\u2010onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic <jats:italic>POLR3A<\/jats:italic> pathogenic variants composed by two cis\u2010acting intronic splicing\u2010altering variants, c.1909\u2009+\u200922G\u2009&gt;\u2009A and c.3337\u201311\u2009T\u2009&gt;\u2009C. The two healthy siblings had wild\u2010type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the <jats:italic>POLR3A<\/jats:italic> gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann\u2010Rautenstrauch syndrome, a severe progeroid <jats:italic>POLR3A<\/jats:italic>\u2010associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype\u2013phenotype correlation in <jats:italic>POLR3A<\/jats:italic>\u2010related disorders.<\/jats:p>","DOI":"10.1111\/cge.13929","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T06:22:42Z","timestamp":1611555762000},"page":"713-718","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Two intronic cis\u2010acting variants in both alleles of the <scp><i>POLR3A<\/i><\/scp> gene cause progressive spastic ataxia with hypodontia"],"prefix":"10.1111","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5354-9134","authenticated-orcid":false,"given":"Avi","family":"Fellner","sequence":"first","affiliation":[{"name":"Raphael Recanati Genetics Institute Rabin Medical Center, Beilinson Campus  Petah Tikva Israel"},{"name":"Department of Neurology Rabin Medical Center, Beilinson Campus  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Lossos","sequence":"additional","affiliation":[{"name":"Department of Neurology Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Kogan","sequence":"additional","affiliation":[{"name":"Department of Neurology Rabin Medical Center, Beilinson Campus  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zohar","family":"Argov","sequence":"additional","affiliation":[{"name":"Department of Neurology Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Gonzaga\u2010Jauregui","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center  Tarrytown NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan R.","family":"Shuldiner","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center  Tarrytown NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malak","family":"Darawshe","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine Tel\u2010Aviv University  Tel\u2010Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lily","family":"Bazak","sequence":"additional","affiliation":[{"name":"Raphael Recanati Genetics Institute Rabin Medical Center, Beilinson Campus  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Lidzbarsky","sequence":"additional","affiliation":[{"name":"Raphael Recanati Genetics Institute Rabin Medical Center, Beilinson Campus  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noam","family":"Shomron","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine Tel\u2010Aviv University  Tel\u2010Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Basel\u2010Salmon","sequence":"additional","affiliation":[{"name":"Raphael Recanati Genetics Institute Rabin Medical Center, Beilinson Campus  Petah Tikva Israel"},{"name":"Sackler Faculty of Medicine Tel\u2010Aviv University  Tel\u2010Aviv Israel"},{"name":"Felsenstein Medical Research Center  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yael","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Raphael Recanati Genetics Institute Rabin Medical Center, Beilinson Campus  Petah Tikva Israel"},{"name":"Sackler Faculty of Medicine Tel\u2010Aviv University  Tel\u2010Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2012.09.010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw263"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.006271"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.07.014"},{"key":"e_1_2_9_6_1","unstructured":"BernardG VanderverA.POLR3\u2010related leukodystrophy. 2012 Aug 2 [updated 2017 May 11]. In: Adam MP Ardinger HH Pagon RA Wallace SE Bean LJH Mirzaa G Amemiya A eds. GeneReviews\u00ae [Internet]. Seattle (WA): University of Washington Seattle; 1993\u20102021.https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK99167\/"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.1963"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2012.07.005"},{"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":"10.1002\/(SICI)1096-8628(20000117)90:2<131::AID-AJMG9>3.0.CO;2-E"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx095"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09574-9"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-019-00602-4"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-019-0487-1"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0343-7"},{"issue":"1","key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1093\/bioinformatics\/btv547","article-title":"CLAMMS: a scalable algorithm for calling common and rare copy number variants from exome sequencing data","volume":"32","author":"Packer JS","year":"2016","journal-title":"Bioinformatics"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz041"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1341"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.12945"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.13929","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.13929","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.13929","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T14:07:46Z","timestamp":1693577266000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.13929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,15]]},"references-count":20,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1111\/cge.13929"],"URL":"https:\/\/doi.org\/10.1111\/cge.13929","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,15]]},"assertion":[{"value":"2020-11-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}