Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients

Paula Saffie-Awad; Abraham Moller; Kensuke Daida; Pilar Alvarez Jerez; Zhongbo Chen; Zachary B Anderson; Mariam Isayan; Kimberly Paquette; Sophia B Gibson; Madison Fulcher; Abigail Miano-Burkhardt; Laksh Malik; Breeana Baker; Paige Jarreau; Henry Houlden; Mina Ryten; Bida Gu; Mark J P Chaisson; Danny E Miller; Pedro Chaná-Cuevas; Cornelis Blauwendraat; Andrew B Singleton; Kimberley J Billingsley

doi:10.1002/mds.30242

Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients

Mov Disord. 2025 Jun 3. doi: 10.1002/mds.30242. Online ahead of print.

Authors

Paula Saffie-Awad¹, Abraham Moller², Kensuke Daida³, Pilar Alvarez Jerez^{2

4}, Zhongbo Chen^{4

5

6}, Zachary B Anderson⁷, Mariam Isayan⁸, Kimberly Paquette², Sophia B Gibson^{7

9}, Madison Fulcher³, Abigail Miano-Burkhardt³, Laksh Malik², Breeana Baker², Paige Jarreau², Henry Houlden¹⁰, Mina Ryten^{11

12

13

14}, Bida Gu¹⁵, Mark J P Chaisson¹⁵, Danny E Miller^{9

16

17}, Pedro Chaná-Cuevas¹⁸, Cornelis Blauwendraat^{2

3}, Andrew B Singleton^{2

3}, Kimberley J Billingsley²

Affiliations

¹ Clínica Santa María, Santiago, Chile.
² Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
³ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁵ Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁶ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
⁷ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
⁸ Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia.
⁹ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹⁰ Department of Neuromuscular Disease, Queen Square Institute of Neurology, UCL, London, UK.
¹¹ Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK.
¹² NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK.
¹³ UK Dementia Research Institute, University of Cambridge, Cambridge, UK.
¹⁴ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹⁵ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, California, USA.
¹⁶ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
¹⁷ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, Washington, USA.
¹⁸ Centro de Trastornos del Movimiento, Facultad de Ciencias M ́edicas, Universidad de Santiago de Chile, Santiago, Chile.

PMID: 40459184
DOI: 10.1002/mds.30242

Abstract

Background: Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. The GGC repeat expansion in ZFHX3, responsible for spinocerebellar ataxia type 4 (SCA4), has only been described in individuals of Northern Europeandescent.

Objective: Uncover the genetic etiology of suspected hereditary movement disorders.

Methods: We performed Oxford Nanopore long-read genome sequencing on 15 individuals with suspected hereditary movement disorders. Using variant calling and ancestry inference tools.

Results: We identified ZFHX3 GGC expansions (47-55 repeats) in 4 patients with progressive ataxia, polyneuropathy, and vermis atrophy. One presented with rapidly progressive parkinsonism-ataxia, expanding the known phenotype. Longer expansions correlated with earlier onset and severity. All carriers shared single nucleotide variants (SNVs) associated with the Swedish founder haplotype, and methylation analysis confirmed allele-specific hypermethylation.

Conclusion: These represent the first SCA4 cases identified outside Northern Europe. Our findings highlight the value of long-read sequencing in resolving undiagnosed movement disorders. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Latin American Population; Long Read Sequencing; Spinocerebellar Ataxias; Tandem Repeat Expansions; ZFHX3 gene.

Published 2025. This article is a U.S. Government work and is in the public domain in the USA. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract

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