Scholarlink

<p>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 <i>HTT</i>, 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 (<i>n</i> = 134), UK Biobank (<i>n</i> = 26), and a clinically ascertained multicenter Spanish cohort recruited by the Spanish Study Group for Genetics of Chorea (SSGGC) (<i>n</i> = 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 <i>JPH3</i> expansion in a patient of Black race and <i>c9orf72</i> 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>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Unraveling the genetic architecture of non-Huntington chorea: a biobank-scale study of rare variants and repeat expansions

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月9日

查看全文
  • 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,
  • Pau Pastor

摘要

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.