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

Author

Listed:
  • 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)
    ISCIII)

  • Montserrat Ruiz

    (Bellvitge Biomedical Research Institute (IDIBELL)
    ISCIII)

  • Moisés Morales de la Prida

    (Bellvitge Biomedical Research Institute (IDIBELL)
    Bellvitge University Hospital)

  • Carlos Casasnovas

    (Bellvitge Biomedical Research Institute (IDIBELL)
    ISCIII
    Bellvitge University Hospital)

  • Kerstin Becker

    (Faculty of Medicine and University Hospital Cologne)

  • Ulla Roggenbuck

    (University of Duisburg-Essen)

  • Sonali Pechlivanis

    (University of Duisburg-Essen
    German Research Center for Environmental Health)

  • Frank J. Kaiser

    (University Duisburg-Essen
    Universitätsklinikum Essen)

  • Matthis Synofzik

    (Center for Neurology & Hertie Institute for Clinical Brain Research Tübingen
    German Center for Neurodegenerative Diseases (DZNE))

  • Thomas Wirth

    (Hôpital de Hautepierre
    INSERM-U964/CNRS-UMR7104/Université de Strasbourg
    Université de Strasbourg)

  • Mathieu Anheim

    (Hôpital de Hautepierre
    INSERM-U964/CNRS-UMR7104/Université de Strasbourg
    Université de Strasbourg)

  • Tobias B. Haack

    (University of Tübingen
    University of Tübingen)

  • Paul J. Lockhart

    (The University of Melbourne)

  • Karl-Heinz Jöckel

    (University of Duisburg-Essen)

  • Aurora Pujol

    (Bellvitge Biomedical Research Institute (IDIBELL)
    ISCIII
    Catalan Institution of Research and Advanced Studies (ICREA))

  • Stephan Klebe

    (University Duisburg-Essen)

  • Dagmar Timmann

    (University Duisburg-Essen)

  • Christel Depienne

    (University Duisburg-Essen)

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.

Suggested Citation

  • Lars Mohren & Friedrich Erdlenbruch & Elsa Leitão & Fabian Kilpert & G. Sebastian Hönes & Sabine Kaya & Christopher Schröder & Andreas Thieme & Marc Sturm & Joohyun Park & Agatha Schlüter & Montserrat, 2024. "Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52148-1
    DOI: 10.1038/s41467-024-52148-1
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    References listed on IDEAS

    as
    1. Rahel T. Florian & Florian Kraft & Elsa Leitão & Sabine Kaya & Stephan Klebe & Eloi Magnin & Anne-Fleur van Rootselaar & Julien Buratti & Theresa Kühnel & Christopher Schröder & Sebastian Giesselmann , 2019. "Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Mark A. Corbett & Thessa Kroes & Liana Veneziano & Mark F. Bennett & Rahel Florian & Amy L. Schneider & Antonietta Coppola & Laura Licchetta & Silvana Franceschetti & Antonio Suppa & Aaron Wenger & Da, 2019. "Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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