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T.B.H. was supported by the DFG, grants 418081722 and 433158657. J. Park was supported by the Else Kröner-Fresenius-Stiftung Clinician Scientist program 'PRECISE.net'. NGS methods were performed with the support of the DFG-funded NGS Competence Center Tübingen (INST 37/1049-1). We thank our colleagues from the Clinical Long-read Genome Initiative (lonGER consortium) for valuable discussion and exchange on methodological aspects of ONT LR-GS. Author notes These authors contributed equally: Karla P. Figueroa, Caspar Gross, Elena Buena-Atienza. Department of Neurology, University of Utah, Salt Lake City, UT, USA Karla P. Figueroa, Sharan Paul, Mandi Gandelman, Daniel R. Scoles & Stefan M. Pulst Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany Caspar Gross, Elena Buena-Atienza, Marc Sturm, Nicolas Casadei, Jakob Admard, Joohyun Park, Claudia Dufke, Olaf Riess, Stephan Ossowski & Tobias B. Haack NGS Competence Center Tübingen, Tübingen, Germany Caspar Gross, Elena Buena-Atienza, Nicolas Casadei, Jakob Admard, Olaf Riess, Stephan Ossowski & Tobias B. Haack Institute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Germany Naseebullah Kakar, Christine Zühlke, Yorck Hellenbroich, Jelena Pozojevic, Saranya Balachandran, Kristian Händler & Malte Spielmann Department of Biotechnology, FLS&I, BUITEMS, Quetta, Pakistan Naseebullah Kakar Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Simone Zittel & Laura Herrmann Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen, Germany Dagmar Timmann & Friedrich Erdlenbruch Practice of Neurology, Magdeburg, Germany Thomas Feindt Institute of Human Genetics, University Hospital Magdeburg and Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany Martin Zenker Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-Universität München, Munich, Germany Thomas Klopstock German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Thomas Klopstock Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Thomas Klopstock Veterans Affairs Medical Center, Albany, NY, USA Arnulf Koeppen DZHK (German Centre for Cardiovascular Research), partner site Hamburg, Lübeck, Kiel, Lübeck, Germany Malte Spielmann Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, Tübingen, Germany Stephan Ossowski Clinical Neurosciences Center, University of Utah Hospitals and Clinics, Salt Lake City, UT, USA Stefan M. Pulst K.P.F., M. Spielmann, O.R., S.O., T.B.H. and S.M.P. jointly supervised the research. K.P.F., N.C. and S.M.P. conceptualized and designed the experiments. K.P.F., C.G., E.B.-A., S.P., M.G., T.B.H., N.K., J. Park, K.H., C.D. and A.K. performed the experiments. K.P.F. performed real-time PCR analyses. S.P. performed western blotting. M.G. produced iPS cells and iPS cell-derived neurons. M.G. and A.K. performed immunohistological stains. K.P.F., S.P., M.G., J. Park, D.R.S., S.O. and T.B.H. performed statistical tests. K.P.F., E.B.-A., S.P., M.G., N.K., M. Sturm, N.C., J.A., Y.H., J. Pozojevic, S.B., T.F. and S.O. performed data analyses. K.P.F., N.K., C.Z., Y.H., S.Z., D.T., F.E., L.H., M.Z., T.K., O.R. and S.M.P. contributed patient materials or patient data. K.P.F., E.B.-A., N.K., M. Sturm, N.C., J. Park, D.R.S., A.K., M. Spielmann, O.R., S.O., T.B.H. and S.M.P. contributed to writing the paper. The authors declare no competing interests. Nature Genetics thanks Jianwen Deng, Clevio Nobrega and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions Figueroa, K.P., Gross, C., Buena-Atienza, E. et al. A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.
Nat Genet (2024). https://doi.org/10.1038/s41588-024-01719-5 Download citation Received: 03 November 2023 Accepted: 18 March 2024 Published: 29 April 2024 DOI: https://doi.org/10.1038/s41588-024-01719-5Data availability
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Extended Data Table 1 P-values associated with charts in Figure 4dExtended Data Table 2 P-values associated with charts in Figure 5eSupplementary information
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