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

Autor: Mohren L; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Erdlenbruch F; Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Essen, Germany., Leitão E; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Kilpert F; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Hönes GS; Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Kaya S; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Schröder C; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Thieme A; Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Essen, Germany., Sturm M; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Park J; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Schlüter A; Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain., Ruiz M; Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain., Morales de la Prida M; Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.; Neuromuscular Unit, Neurology Department, Bellvitge University Hospital, Barcelona, Spain., Casasnovas C; Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.; Neuromuscular Unit, Neurology Department, Bellvitge University Hospital, Barcelona, Spain., Becker K; Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Roggenbuck U; Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Pechlivanis S; Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Institute of Asthma and Allergy Prevention, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Kaiser FJ; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.; Essener Zentrum für Seltene Erkrankungen (EZSE), Universitätsklinikum Essen, Essen, Germany., Synofzik M; Division Translational Genomics of Neurodegenerative Diseases, Center for Neurology & Hertie Institute for Clinical Brain Research Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany., Wirth T; Service de Neurologie, Département de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1, Avenue Molière, Strasbourg, Cedex, France.; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France.; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France., Anheim M; Service de Neurologie, Département de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1, Avenue Molière, Strasbourg, Cedex, France.; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France.; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France., Haack TB; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany., Lockhart PJ; Bruce Lefroy Centre, Murdoch Children's Research Institute; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia., Jöckel KH; Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Pujol A; Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain., Klebe S; Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Essen, Germany., Timmann D; Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Essen, Germany., Depienne C; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany. christel.depienne@uk-essen.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 03; Vol. 15 (1), pp. 7665. Date of Electronic Publication: 2024 Sep 03.
DOI: 10.1038/s41467-024-52148-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: