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Here, we report the third patient worldwide with pathogenic variants in <jats:italic>POLR3K<\/jats:italic> and clinical features consistent with POLR3\u2010HLD. The female patient presented with mild intellectual and behavioural disturbances in childhood, as well as growth delay, with brain MRI revealing diffuse hypomyelination and a pattern consistent with POLR3\u2010HLD. In adolescence, she manifested minor motor dysfunction. Next\u2010generation sequencing revealed a paternally inherited missense variant in <jats:italic>POLR3K<\/jats:italic> (c.322G&gt;T; p.D108Y) and a maternally inherited large deletion, spanning approximately 17.8\u2009kb from chr16:30,362\u201048,162. The missense variant is located at the C\u2010terminus position of the protein and is predicted to impair residue interactions and cause steric interference in enzyme conformational changes. The large deletion encompasses the third and last exon of <jats:italic>POLR3K<\/jats:italic>, leading to a likely amorphic truncated protein product lacking the final 42 amino acids from the total 108 amino acid\u2013length protein. Studies of RNA\u2010level expression showed a significant reduction in the levels of <jats:italic>POLR3K<\/jats:italic> RNA in the patient compared to the control. In considering whether the transcriptional function of Pol III was affected, the expression of several Pol III\u2010transcribed RNAs was measured, where the levels of several distinct tRNAs were significantly reduced in the patient while the expression of other RNA transcripts was not decreased, suggesting that Pol III retains partial function. This study provides further evidence for the association of pathogenic variants in <jats:italic>POLR3K<\/jats:italic> with POLR3\u2010HLD, expanding the spectrum of pathogenic variants in genes encoding for Pol III subunits associated with this disease.<\/jats:p>","DOI":"10.1155\/2024\/8807171","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T14:39:30Z","timestamp":1722436770000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel Pathogenic Variants in <i>POLR3K<\/i> Cause POLR3\u2010Related Leukodystrophy"],"prefix":"10.1155","volume":"2024","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6881-7573","authenticated-orcid":false,"given":"Stefanie","family":"Perrier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-2365","authenticated-orcid":false,"given":"Julia","family":"Macintosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9763-1815","authenticated-orcid":false,"given":"Agata D.","family":"Misiaszek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8412-9925","authenticated-orcid":false,"given":"Kether","family":"Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4666-1755","authenticated-orcid":false,"given":"Luan T.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-8337","authenticated-orcid":false,"given":"Christoph W.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4016-5021","authenticated-orcid":false,"given":"Tomi","family":"Pastinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6933-4138","authenticated-orcid":false,"given":"Gustavo H. 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