| Title: | Unraveling the genetic architecture of non-Huntington chorea: a biobank-scale study of rare variants and repeat expansions |
| Journal: | npj Genomic Medicine |
| Published: | 9 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41957010/ |
| DOI: | https://doi.org/10.1038/s41525-026-00567-y |
Publication 18054
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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.</p>
26 Authors
- Fulya Akçimen
- Monica Diez-Fairen
- Ignacio Alvarez
- Victor Puente
- Spencer Grant
- Jorge Hernandez-Vara
- Marzieh Khani
- Mariateresa Buongiorno
- Félix Javier Jiménez-Jiménez
- José A. G. Agúndez
- Miquel Aguilar
- Esther Cubo
- Jesus Perez
- Javier Pagonabarraga
- Núria Caballol
- Asuncion Avila
- Jinhui Ding
- Elena García-Martín
- Hortensia Alonso-Navarro
- Yaroslau Compta
- Carlos Cruchaga
- Katrin Beyer
- J. Raphael Gibbs
- Andrew Singleton
- Sara Bandres-Ciga
- Pau Pastor
1 Application
| Application ID | Title |
|---|---|
| 33601 | Dissecting the genetic architecture of neurodegenerative diseases |
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