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

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 Details

Journal
Nature Communications
Published
2024-09-03
DOI
https://doi.org/10.1038/s41467-024-52148-1
Citations
28
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
Field-Weighted Citation Impact
7.51

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article

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

Elsa Leitão, Paul J. Lockhart, Sonali Pechlivanis, Moisés Morales de la Prida et al.
28 citations
Nature Communications
Genetic Neurodegenerative Diseases
7.51
article

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

Elsa Leitão, Paul J. Lockhart, Sonali Pechlivanis, Moisés Morales de la Prida, Tobias B. Haack, Sabine Kaya, Christel Depienne, Ulla Roggenbuck, Carlos Casasnovas, Stephan Klebe, Montserrat Ruíz, Matthis Synofzik, Kerstin Becker, Agatha Schlüter, Frank J. Kaiser, Karl‐Heinz Jöckel, Dagmar Timmann, Friedrich Erdlenbruch, Georg Sebastian Hönes, Andreas Thieme, Fabian Kilpert, Aurora Pujol, Marc Sturm, Mathieu Anheim, Thomas Wirth, Lars Mohren, Joohyun Park, Christopher Schröder
article en
28 citations

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.

Nature CommunicationsVol. 15(1)
Institució Catalana de Recerca i Estudis Avançats (ES), Centre National de la Recherche Scientifique (FR), Inserm (FR), The University of Melbourne (AU), University of Cologne (DE), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Bellvitge University Hospital (ES), Helmholtz Zentrum München (DE), Institut de génétique et de biologie moléculaire et cellulaire (FR), Institut d'Investigació Biomédica de Bellvitge (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Centro de Investigación Biomédica en Red (ES), Essen University Hospital (DE), Hertie Institute for Clinical Brain Research (DE), Hôpitaux Universitaires de Strasbourg (FR), Murdoch Children's Research Institute (AU), University Hospital Cologne (DE), University of Duisburg-Essen (DE), Université de Strasbourg (FR), University of Tübingen (DE)
Centres de Recerca de Catalunya, Fundación Hesperia, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Generalitat de Catalunya, Else Kröner-Fresenius-Stiftung, Instituto de Salud Carlos III, European Regional Development Fund
Good health and well-being
Openalex Percentile: Top 2%
Genetic Neurodegenerative Diseases
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