Abstract
Chorea can arise from genetic, metabolic, pharmacologic, and autoimmune causes. In clinical practice, however, non-genetic causes are rare. The most common genetic cause is a CAG repeat expansion in HTT, leading to Huntington’s disease (HD). Beyond HD, systematic studies have been lacking and many individuals with non-HD chorea remain without a molecular diagnosis. We conducted whole-exome and genome sequencing analysis on 190 non-HD chorea cases, leveraging data from the All of Us Research Program (n = 134), UK Biobank (n = 26), and a clinically ascertained multicenter Spanish cohort recruited by the Spanish Study Group for Genetics of Chorea (SSGGC) (n = 30). Variant calling was performed without pre-filtering based on a disease or gene list, and variants were clinically contextualized using OMIM, ClinVar, and in silico predictions. We identified thirteen protein-altering variants, including six previously described as pathogenic or likely pathogenic. Notably, we identified a pathogenic JPH3 expansion in a patient of Black race and c9orf72 expansions in individuals of European and South Asian ancestry. These findings explained 23% of cases in the SSGGC, 12% in UK Biobank, and 4% in All of Us. Our results broaden the genetic architecture of non-HD chorea and highlight the value of multi-ancestry genomic approaches for rare movement disorders.
Data availability
Publicly available data consortia include All of Us Research Program (https://www.researchallofus.org/register/) and UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/register), in which data can be accessed after applying. We have received an exception to the Data and Statistics Dissemination Policy from the All of Us Resource Access Board.
Code availability
A repository of all other code used for processing and analyzing is publicly available at https://github.com/fulyaakcimen/Genetic-characterization-of-non-Huntington-chorea.
References
Fahn, S., Jankovic, J. & Hallett, M. Principles and Practice of Movement Disorders. (Churchill Livingstone, 2011).
Saft, C. et al. Differential diagnosis of chorea (guidelines of the German Neurological Society). Neurol. Res. Pract. 5, 63 (2023).
Caron, N. S., Wright, G. E. B. & Hayden, M. R. Huntington Disease. in GeneReviews® [Internet] (University of Washington, Seattle, 2020).
Hensman Moss, D. J. et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology 82, 292–299 (2014).
Friedman, D., Digre, K. & Liu, G. Author response. Neurology 82, 1753 (2014).
Margolis, R. L. et al. A disorder similar to Huntington’s disease is associated with a novel CAG repeat expansion. Ann. Neurol. 50, 373–380 (2001).
Schneider, S. A. & Bird, T. Huntington’s disease, Huntington’s disease look-alikes, and benign hereditary chorea: What’s new? Mov. Disord. Clin. Pract. 3, 342–354 (2016).
Martinez-Ramirez, D., Walker, R. H., Rodríguez-Violante, M. & Gatto, E. M. Rare Movement Disorders Study Group of International Parkinson’s Disease. Review of hereditary and acquired rare choreas. Tremor Other Hyperkinet. Mov. (N.Y.) 10, 24 (2020).
Cincotta, M. C. & Walker, R. H. Recent advances in non-Huntington’s disease choreas. Parkinsonism Relat. Disord. 122, 106045 (2024).
van Gaalen, J., Giunti, P. & van de Warrenburg, B. P. Movement disorders in spinocerebellar ataxias. Mov. Disord. 26, 792–800 (2011).
Rossi, M. et al. Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review. Mov. Disord. 38, 368–377 (2023).
Walker, R. H. The non-Huntington disease choreas: Five new things. Neurol. Clin. Pract. 6, 150–156 (2016).
Garcia Ruiz, P. J. et al. The enduring enigma of sporadic chorea: A single center case series. Tremor Other Hyperkinet Mov. (N.Y.) 13, 33 (2023).
All of Us Research Program Investigators et al. The ‘All of Us’ Research Program. N. Engl. J. Med. 381, 668–676 (2019).
Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).
Patel, N. J. & Jankovic, J. NKX2-1-Related Disorders. in GeneReviews® [Internet] (University of Washington, Seattle, 2023).
Breedveld, G. J. et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum. Mol. Genet 11, 971–979 (2002).
Asmus, F. et al. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology 64, 1952–1954 (2005).
Balicza, P. et al. NKX2-1 New Mutation Associated With Myoclonus, Dystonia, and Pituitary Involvement. Front Genet 9, 335 (2018).
Chen, W.-J. et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat. Genet. 43, 1252–1255 (2011).
Schubert, J. et al. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum. Mutat. 33, 1439–1443 (2012).
Carecchio, M. et al. ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients. Parkinsonism Relat. Disord. 41, 37–43 (2017).
Mencacci, N. E. et al. ADCY5 mutations are another cause of benign hereditary chorea. Neurology 85, 80–88 (2015).
Kaur, G., Gao, X., Rodriguez, W. & Chand, P. A unique case of late adult onset dyskinesia due to adenylyl cyclase 5 mutation (P6). Neurology 102, 6 (2024).
Quazza, F. et al. Atypical ADCY5-related movement disorders: Highlighting adolescent/adult-onset cervical dystonia. Parkinsonism Relat. Disord. 132, 107274 (2025).
Mir, Y. R. et al. Exome sequencing and molecular dynamics simulation characterizes a compound heterozygous GCDH missense variant leading to glutaric aciduria type 1 in a paediatric patient from Jammu and Kashmir, India. Gene Rep. 38, 102092 (2025).
Hughes, D. A. & Pastores, G. M. Gaucher Disease. in GeneReviews® [Internet] (University of Washington, Seattle, 2023).
Borroni, B. et al. Choreo-athetosis in LRRK2 R1441C mutation: expanding the clinical phenotype. Clin. Neurol. Neurosurg. 115, 2217–2218 (2013).
Stamelou, M. et al. The phenotypic spectrum of DYT24 due to ANO3 mutations. Mov. Disord. 29, 928–934 (2014).
Parlar, S. C., Grenn, F. P., Kim, J. J., Baluwendraat, C. & Gan-Or, Z. Classification of GBA1 Variants in Parkinson’s Disease: The GBA1-PD Browser. Mov. Disord. 38, 489–495 (2023).
Schipper, H. M. Neurodegeneration with brain iron accumulation - clinical syndromes and neuroimaging. Biochim Biophys. Acta 1822, 350–360 (2012).
Romito, L. M. et al. ANO3 as a Cause of Early-Onset Chorea Combined with Dystonia: Illustration of Phenotypic Evolution. Mov. Disord. 39, 220–221 (2024).
Ousingsawat, J. et al. Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia. Brain 147, 1982–1995 (2024).
Percetti, M. et al. The Clinical Spectrum of ANO3-Report of a New Family and Literature Review. Mov. Disord. Clin. Pr. 11, 289–297 (2024).
Chen, Y.-Z. et al. Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5. Arch. Neurol. 69, 630–635 (2012).
Steel, D. et al. Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities. Ann. Neurol. 88, 867–877 (2020).
Thomsen, M., Lange, L. M., Klein, C. & Lohmann, K. MDSGene: Extending the List of Isolated Dystonia Genes by VPS16, EIF2AK2, and AOPEP. Mov. Disord. 38, 507–508 (2023).
Monfrini, E. et al. Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia. Mov. Disord. Clin. Pr. 11, 87–93 (2024).
Beyzaei, Z., Mehrzadeh, A., Hashemi, N. & Geramizadeh, B. The mutation spectrum and ethnic distribution of Wilson disease, a review. Mol. Genet Metab. Rep. 38, 101034 (2024).
Alonso-Castellano, P. et al. Low penetrance of frequent ATP7B mutations explains the low prevalence of Wilson disease. Lessons from real-life registries. Dig. Liver Dis. 57, 443–449 (2025).
Pérez-Oliveira, S. et al. Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies. Mov. Disord. 37, 1841–1849 (2022).
Ibañez, K. et al. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 21, 234–245 (2022).
Merico, D. et al. variant c.1934T > G p.Met645Arg causes Wilson disease by promoting exon 6 skipping. NPJ Genom. Med 5, 16 (2020).
Clinical Approach to the Diagnostic Evaluation of Chorea - Practical Neurology.
All of Us Research Program Genomics Investigators Genomic data in the All of Us Research Program. Nature 627, 340–346 (2024)..
Vitale, D. et al. GenoTools: an open-source Python package for efficient genotype data quality control and analysis. G3 (Bethesda) 15, jkae268 (2025).
Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).
Chatterji, S. & Pachter, L. Reference based annotation with GeneMapper. Genome Biol. 7, R29 (2006).
Dolzhenko, E. et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res 27, 1895–1903 (2017).
Dolzhenko, E. et al. ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions. Bioinformatics 35, 4754–4756 (2019).
Dolzhenko, E. et al. REViewer: haplotype-resolved visualization of read alignments in and around tandem repeats. Genome Med 14, 84 (2022).
Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinforma. 43, 11.10.1–11.10.33 (2013).
Harrison, S. M. et al. Harmonizing variant classification for return of results in the All of Us Research Program. Hum. Mutat. 43, 1114–1121 (2022).
Venner, E. et al. Whole-genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program. Genome Med 14, 34 (2022).
Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38, e164 (2010).
Ioannidis, N. M. et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am. J. Hum. Genet 99, 877–885 (2016).
Cheng, J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492 (2023).
Sundaram, L. et al. Author Correction: Predicting the clinical impact of human mutation with deep neural networks. Nat. Genet 51, 364 (2019).
Jagadeesh, K. A. et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat. Genet 48, 1581–1586 (2016).
Chen, S. et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625, 92–100 (2024).
Amendola, L. M. et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res 25, 305–315 (2015).
Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet 46, 310–315 (2014).
Acknowledgements
We thank Paige Brown Jarreau and Suleyman Can Akerman for their meticulous editing of this manuscript and figures. This work was supported in part by the Intramural Research Program of the NIH, the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project numbers ZO1 AG000535 and ZIA AG000949. The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. This work utilized the computational resources of the NIH HPC Biowulf cluster. (http://hpc.nih.gov). The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants. This research has been conducted using the UK Biobank Resource under application number 33601.
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Conceptualization and study design: F.A., S.B., and P.P.; Participant recruitment and sample collection: M.D., I.A., V.P., J.H., M.B., F.J.J., J.A.G., M.A., E.C, J.P., J.P., N.C., A.A., E.G., H.A., Y.C., C.C., K.B., P.P.; Manuscript writing: F.A., S.B., and P.P.; Manuscript reviewing and editing: S.G., M.K.; Computational analysis: J.D. and J.R.G.
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Akçimen, F., Diez-Fairen, M., Alvarez, I. et al. Unraveling the genetic architecture of non-Huntington chorea: a biobank-scale study of rare variants and repeat expansions. npj Genom. Med. (2026). https://doi.org/10.1038/s41525-026-00567-y
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DOI: https://doi.org/10.1038/s41525-026-00567-y
