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Mohren, L.* ; Erdlenbruch, F.* ; Leitão, E.* ; Kilpert, F.* ; Hönes, G.S.* ; Kaya, S.* ; Schröder, C.* ; Thieme, A.* ; Sturm, M.* ; Park, J.* ; Schlüter, A.* ; Ruiz, M.* ; Morales de la Prida, M.* ; Casasnovas, C.* ; Becker, K.* ; Roggenbuck, U.* ; Pechlivanis, S. ; Kaiser, F.J.* ; Synofzik, M.* ; Wirth, T.* ; Anheim, M.* ; Haack, T.B.* ; Lockhart, P.J.* ; Jöckel, K.H.* ; Pujol, A.* ; Klebe, S.* ; Timmann, D.* ; Depienne, C.*

Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.

Nat. Commun. 15:7665 (2024)
Publ. Version/Full Text DOI PMC
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Repeat expansions in FGF14 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 FGF14 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 FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180-200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5' 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 23-31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Fibroblast-growth-factor-14 Gene; Circular-dichroism; Frameshift Mutation; Ataxia; Scale; Rna
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 7665 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Asthma and Allergy Prevention (IAP)
Grants Tom Wahlig foundation
Instituto de Salud Carlos III - Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa
La Marato de TV3 Foundation
Hesperia Foundation (Royal House of Spain)
Biomedical Research Networking Center on Rare Diseases (CIBERER)
Autonomous Government of Catalonia
Undiagnosed Rare Diseases Program of Catalonia
DFG Research Unit
Clinician Scientist program PRECISE.net - Else Kroner-Fresenius-Stiftung
German Federal Ministry of Education and Research (BMBF)
DFG
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Research Infrastructure West German Genome Center
University Hospital Essen
CERCA Program/Generalitat de Catalunya