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

Lars Mohren, Friedrich Erdlenbruch, Elsa Leitão, Fabian Kilpert, G. Sebastian Hönes, Sabine Kaya, Christopher Schröder, Andreas Thieme, Marc Sturm, Joohyun Park, Agatha Schlüter, Montserrat Ruiz, Moisés Morales de la Prida, Carlos Casasnovas, Kerstin Becker, Ulla Roggenbuck, Sonali Pechlivanis, Frank J. Kaiser, Matthis Synofzik, Thomas Wirth, Mathieu Anheim, Tobias B. Haack, Paul J. Lockhart, Karl-Heinz Jöckel, Aurora Pujol, Stephan Klebe, Dagmar Timmann and Christel Depienne ()
Additional contact information
Lars Mohren: University Duisburg-Essen
Friedrich Erdlenbruch: University Duisburg-Essen
Elsa Leitão: University Duisburg-Essen
Fabian Kilpert: University Duisburg-Essen
G. Sebastian Hönes: University of Duisburg-Essen
Sabine Kaya: University Duisburg-Essen
Christopher Schröder: University Duisburg-Essen
Andreas Thieme: University Duisburg-Essen
Marc Sturm: University of Tübingen
Joohyun Park: University of Tübingen
Agatha Schlüter: Bellvitge Biomedical Research Institute (IDIBELL)
Montserrat Ruiz: Bellvitge Biomedical Research Institute (IDIBELL)
Moisés Morales de la Prida: Bellvitge Biomedical Research Institute (IDIBELL)
Carlos Casasnovas: Bellvitge Biomedical Research Institute (IDIBELL)
Kerstin Becker: Faculty of Medicine and University Hospital Cologne
Ulla Roggenbuck: University of Duisburg-Essen
Sonali Pechlivanis: University of Duisburg-Essen
Frank J. Kaiser: University Duisburg-Essen
Matthis Synofzik: Center for Neurology & Hertie Institute for Clinical Brain Research Tübingen
Thomas Wirth: Hôpital de Hautepierre
Mathieu Anheim: Hôpital de Hautepierre
Tobias B. Haack: University of Tübingen
Paul J. Lockhart: The University of Melbourne
Karl-Heinz Jöckel: University of Duisburg-Essen
Aurora Pujol: Bellvitge Biomedical Research Institute (IDIBELL)
Stephan Klebe: University Duisburg-Essen
Dagmar Timmann: University Duisburg-Essen
Christel Depienne: University Duisburg-Essen

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52148-1

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