Genetic Variation Analysis of Essential Tremor: Insights from the China Essential Tremor Alliance Cohort

作者：Mingqiang Li, Yuwen Zhao, Yuzheng Wang, Runcheng He, Guohua Zhao, Xuejing Wang, Yanming Xu, Hongmei Cao, Hong Liu, Chengjie Mao, Heng Wu, Di Wei, Yuhu Zhang, Puqing Wang, Wei Huang, Yan Xu, Oumei Cheng, Guiyun Cui, Zhentao Zhang, Kezhong Zhang, Yiwen Wu, Tao Chen, Nian Xiong, Lifang Lei, Xun Zhou, Hongxu Pan, Xiaomei Duan, Sheng Zeng, Dong Chang, Liang Jin, Jinchen Li, Qian Xu, Zhenhua Liu, Jifeng Guo, Chunyu Wang, Tao Wang, Chun‐Feng Liu, Jun Liu, Qiying Sun, Beisha Tang, China Essential Tremor Alliance (CETA) · 发表于：Movement Disorders · 年份：2025 · DOI：10.1002/mds.70106 · 被引用次数：3 · 研究领域：Neurological disorders and treatments、Glycogen Storage Diseases and Myoclonus、Parkinson's Disease Mechanisms and Treatments

BACKGROUND AND OBJECTIVE: Essential tremor (ET) is a common movement disorder (MD) with significant genetic contributions, yet its genetic basis remains poorly understood. To clarify ET's genetic architecture and improve clinical diagnostics, we investigated pathogenic variants and their clinical implications in a large Chinese cohort. METHODS: Whole-genome sequencing was conducted on 3097 Chinese patients with ET and 2050 healthy control subjects. We analyzed variants within 26 known ET-associated genes and 437 broader MD-associated genes. Variants were classified as pathogenic or likely pathogenic (P/LP) following American College of Medical Genetics and Genomics guidelines. RESULTS: Twenty-six patients with ET (0.84%) harbored P/LP variants in ET-associated genes, involving eight genes and 24 distinct variants, with CACNA1G (n = 9) and GPR151 (n = 4) most frequently implicated. Only two patients carried previously reported ET-associated variants. Genetic segregation analysis in five families did not confirm clear cosegregation. In addition, 83 patients (2.68%) carried P/LP variants in broader MD-associated genes, notably, GSN (n = 7), FAT2 (n = 6), and FIG4 (n = 6). Clinical follow-up rediagnosed six individuals carrying GCH1, SGCE, GRN, and NOTCH3 variants with alternative MDs, and two individuals with PRKN and PSEN1 variants developed additional MDs. The remaining patients maintained ET diagnosis without MD progression. Six individuals (0.24%) were identified with Klinef...