{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:29:01Z","timestamp":1793831341849,"version":"4.6.1"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T00:00:00Z","timestamp":1725321600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T00:00:00Z","timestamp":1725321600000},"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":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Repeat expansions in\n                    <jats:italic>FGF14<\/jats:italic>\n                    cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect\n                    <jats:italic>FGF14<\/jats:italic>\n                    expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare\n                    <jats:italic>FGF14<\/jats:italic>\n                    expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180\u2013200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5\u2019 flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23\u201331% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-52148-1","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T09:03:06Z","timestamp":1725354186000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8990-7487","authenticated-orcid":false,"given":"Lars","family":"Mohren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0654-836X","authenticated-orcid":false,"given":"Friedrich","family":"Erdlenbruch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5051-9714","authenticated-orcid":false,"given":"Elsa","family":"Leit\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6401-2180","authenticated-orcid":false,"given":"Fabian","family":"Kilpert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5080-7166","authenticated-orcid":false,"given":"G. 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