Identification of GGC Repeat Expansions in ZFHX3 Among Chilean Movement Disorder Patients.
| Title: | Identification of GGC Repeat Expansions in ZFHX3 Among Chilean Movement Disorder Patients. |
|---|---|
| Authors: | Saffie-Awad P; Clínica Santa María, Santiago, Chile.; Moller A; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Daida K; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Jerez PA; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.; Chen Z; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.; Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK 3.; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK.; Anderson ZB; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.; Isayan M; Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia.; Paquette K; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Gibson SB; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.; Fulcher M; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Miano-Burkhardt A; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Malik L; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Baker B; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Jarreau P; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Houlden H; Department of Neuromuscular Disease, Queen Square Institute of Neurology, UCL, London, UK.; Ryten M; Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK.; NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK.; UK Dementia Research Institute at the University of Cambridge, Cambridge, UK.; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.; Gu B; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.; Chaisson MJ; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.; Miller DE; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington 98195, USA.; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, Washington 98195, USA.; Chaná-Cuevas P; Centro de Trastornos del Movimiento, Facultad de Ciencias M' edicas, Universidad de Santiago de Chile, Santiago, Chile.; Blauwendraat C; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Singleton AB; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Billingsley KJ; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. |
| Source: | MedRxiv : the preprint server for health sciences [medRxiv] 2025 Mar 19. Date of Electronic Publication: 2025 Mar 19. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Background: Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. A pathogenic ZFHX3 GGC repeat expansion was recently linked to spinocerebellar ataxia type 4 (SCA4), characterized by progressive ataxia and sensory neuropathy, with all reported cases in individuals of Northern European ancestry.; Methods: We performed Oxford Nanopore Technologies (ONT) genome long-read sequencing (>115 GB per sample) on a total of 15 individuals from Chile; 14 patients with suspected hereditary movement disorders and one unrelated family member. Variants were identified using PEPPER-Margin-DeepVariant 0.8 (SNVs), Sniffles 2.4 (SVs), and Vamos 2.1.3 (STRs). Ancestry was inferred using GenoTools with reference data from the 1000 Genomes Project, Human Genome Diversity Project, and an Ashkenazi Jewish panel. Haplotype analysis was conducted by phasing SNVs within ZFHX3, and methylation profiling was performed with modbamtools.; Results: We identified ZFHX3 GGC repeat expansions (47-55 repeats) in four individuals with progressive ataxia, polyneuropathy, and vermis atrophy. One case presented parkinsonism-ataxia, expanding the phenotype. Longer expansions correlated with earlier onset and greater severity. Hypermethylation was detected on the expanded allele, and haplotype analysis linked ultra-rare ZFHX3 variants to distant Swedish ancestry.; Conclusion: This is the first report of SCA4 outside Northern Europe, confirming a shared founder haplotype and expansion instability. The presence of parkinsonism broadens the clinical spectrum. Comprehensive genetic testing across diverse populations is crucial, and long-read sequencing enhances diagnostic yield by detecting repeat expansions and SNVs in a single assay. |
| Competing Interests: | The authors declare no financial or non-financial conflicts of interest related to this manuscript. |
| Comments: | Update in: Mov Disord. 2025 Jul;40(7):1433-1441. doi: 10.1002/mds.30242.. (PMID: 40459184) |
| Grant Information: | T32 HG000035 United States HG NHGRI NIH HHS; DP5 OD033357 United States OD NIH HHS; ZIA AG000538 United States ImNIH Intramural NIH HHS; P01 AG000538 United States AG NIA NIH HHS; R01 HG011649 United States HG NHGRI NIH HHS; ZIA NS003154 United States ImNIH Intramural NIH HHS; United Kingdom WT_ Wellcome Trust |
| Entry Date(s): | Date Created: 20250401 Latest Revision: 20250829 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11957069 |
| DOI: | 10.1101/2025.03.17.25323863 |
| PMID: | 40166539 |
| Database: | MEDLINE |
Journal Article; Preprint