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Identification of GGC Repeat Expansions in <i>ZFHX3</i> among Chilean Movement Disorder Patients
Indexado
WoS WOS:001500549600001
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


Abstract



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.

Revista



Revista ISSN
Movement Disorders 0885-3185

Métricas Externas



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Disciplinas de Investigación



WOS
Clinical Neurology
Scopus
Sin Disciplinas
SciELO
Sin Disciplinas

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Publicaciones WoS (Ediciones: ISSHP, ISTP, AHCI, SSCI, SCI), Scopus, SciELO Chile.

Colaboración Institucional



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Autores - Afiliación



Ord. Autor Género Institución - País
1 Saffie-Awad, Paula - Clínica Santa María - Chile
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
6 Anderson, Zachary B. - UNIV WASHINGTON - Estados Unidos
7 Isayan, Mariam - Natl Inst Hlth - Armenia
8 Paquette, Kimberly - Natl Inst Aging - Estados Unidos
Natl Inst Neurol Disorders & Stroke - Estados Unidos
9 Gibson, Sophia B. - UNIV WASHINGTON - Estados Unidos
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
16 Ryten, Mina - UCL - Reino Unido
UNIV CAMBRIDGE - Reino Unido
17 Gu, Bida - Univ Southern Calif - Estados Unidos
18 Chaisson, Mark J. P. - Univ Southern Calif - Estados Unidos
19 Miller, Danny E. - UNIV WASHINGTON - Estados Unidos
20 Chana-Cuevas, Pedro - Universidad de Santiago de Chile - Chile
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

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Financiamiento



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)

Muestra la fuente de financiamiento declarada en la publicación.

Agradecimientos



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).

Muestra la fuente de financiamiento declarada en la publicación.