Movement disorders : official journal of the Movement Disorder Society · 2025
Genetic Variation Analysis of Essential Tremor: Insights from the China Essential Tremor Alliance Cohort.
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Li Mingqiang, Zhao Yuwen, Wang Yuzheng, He Runcheng, Zhao Guohua, Wang Xuejing, Xu Yanming, Cao Hongmei, Liu Hong, Mao Chengjie, Wu Heng, Di Wei, Zhang Yuhu, Wang Puqing, Huang Wei, Xu Yan, Cheng Oumei, Cui Guiyun, Zhang Zhentao, Zhang Kezhong, Wu Yiwen, Chen Tao, Xiong Nian, Lei Lifang, Zhou Xun, Pan Hongxu, Duan Xiaomei, Zeng Sheng, Chang Dong, Jin Liang, Li Jinchen, Xu Qian, Liu Zhenhua, Guo Jifeng, Wang Chunyu, Wang Tao, Liu Chunfeng, Liu Jun, Sun Qiying, Tang Beisha, China Essential Tremor Alliance (CETA)
Аннотация
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 Klinefelter's syndrome (47, XXY).
CONCLUSIONS: Our findings underscore ET's genetic heterogeneity. Integrating genetic screening and longitudinal clinical evaluation is critical for precise diagnosis and identifying patients at risk for alternative or concurrent MDs. © 2025 International Parkinson and Movement Disorder Society.
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 Klinefelter's syndrome (47, XXY).
CONCLUSIONS: Our findings underscore ET's genetic heterogeneity. Integrating genetic screening and longitudinal clinical evaluation is critical for precise diagnosis and identifying patients at risk for alternative or concurrent MDs. © 2025 International Parkinson and Movement Disorder Society.