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| Indexado |
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| DOI | 10.1002/MDS.30242 | ||
| Año | 2025 | ||
| Tipo | artículo de investigación |
Citas Totales
Autores Afiliación Chile
Instituciones Chile
% Participación
Internacional
Autores
Afiliación Extranjera
Instituciones
Extranjeras
BackgroundHereditary 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.ObjectiveUncover the genetic etiology of suspected hereditary movement disorders.MethodsWe performed Oxford Nanopore long-read genome sequencing on 15 individuals with suspected hereditary movement disorders. Using variant calling and ancestry inference tools.ResultsWe 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.ConclusionThese 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.
| Ord. | Autor | Género | Institución - País |
|---|---|---|---|
| 1 | Saffie-Awad, Paula | - |
Clínica Santa María - Chile
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| 2 | Moller, Abraham | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos |
| 3 | Daida, Kensuke | - |
Natl Inst Aging - Estados Unidos
|
| 4 | Alvarez Jerez, Pilar | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos UCL - Reino Unido |
| 5 | Chen, Zhongbo | - |
UCL - Reino Unido
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| 6 | Anderson, Zachary B. | - |
UNIV WASHINGTON - Estados Unidos
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| 7 | Isayan, Mariam | - |
Natl Inst Hlth - Armenia
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| 8 | Paquette, Kimberly | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos |
| 9 | Gibson, Sophia B. | - |
UNIV WASHINGTON - Estados Unidos
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| 10 | Fulcher, Madison | - |
Natl Inst Aging - Estados Unidos
|
| 11 | Miano-Burkhardt, Abigail | - |
Natl Inst Aging - Estados Unidos
|
| 12 | Malik, Laksh | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos |
| 13 | Baker, Breeana | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos |
| 14 | Jarreau, Paige | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos |
| 15 | Houlden, Henry | - |
UCL - Reino Unido
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| 16 | Ryten, Mina | - |
UCL - Reino Unido
UNIV CAMBRIDGE - Reino Unido |
| 17 | Gu, Bida | - |
Univ Southern Calif - Estados Unidos
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| 18 | Chaisson, Mark J. P. | - |
Univ Southern Calif - Estados Unidos
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| 19 | Miller, Danny E. | - |
UNIV WASHINGTON - Estados Unidos
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| 20 | Chana-Cuevas, Pedro | - |
Universidad de Santiago de Chile - Chile
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| 21 | Blauwendraat, Cornelis | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos |
| 22 | Singleton, Andrew B. | Hombre |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos |
| 23 | Billingsley, Kimberley J. | - |
Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos NIA - Estados Unidos |
| Fuente |
|---|
| National Institutes of Health |
| Medical Research Council |
| Wellcome Trust |
| National Institute of Neurological Disorders and Stroke |
| Michael J. Fox Foundation |
| Intramural Research Program of the National Institute on Aging (NIA) |
| Center for Alzheimer's and Related Dementias (CARD), within the Intramural Research Program of the NIA |
| National Institute for Health and Care Research (UCL/UCLH Biomedical Research Centre) |
| Agradecimiento |
|---|
| We sincerely thank the patients and their families for their participation in this study. Their invaluable contributions make this research possible. We also acknowledge the support of Oxford Nanopore Technologies staff in generating this dataset, in particular, A. Markham, J. Anderson, and C. Vacher. This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA) and the Center for Alzheimer's and Related Dementias (CARD), within the Intramural Research Program of the NIA and the National Institute of Neurological Disorders and Stroke (ZIANS003154, ZIAAG000538), National Institutes of Health (AG000538). Computational resources were provided by the NIH HPC Biowulf cluster (). Additional support was provided by the National Institutes of Health (DP5OD033357, R01HG011649, 5T32HG000035-29), as well as grants from The Michael J. Fox Foundation, the Medical Research Council, the Wellcome Trust, and the National Institute for Health and Care Research (UCL/UCLH Biomedical Research Centre). |