Chen Yong-Ping, Yu Shi-Hui, Zhang Guo-Hui, Hou Yan-Bing, Gu Xiao-Jing, Ou Ru-Wei, Shen Ying, Song Wei, Chen Xue-Ping, Zhao Bi, Cao Bei, Zhang Ling-Yu, Sun Ming-Ming, Liu Fei-Fei, Wei Qian-Qian, Liu Kun-Cheng, Lin Jun-Yu, Yang Tian-Mi, Yang Jing, Wu Ying, Jiang Zheng, Liu Jiao, Cheng Yang-Fan, Xiao Yi, Su Wei-Ming, Feng Fei, Cai Ying-Ying, Li Shi-Rong, Hu Tao, Yuan Xiao-Qin, Zhou Qing-Qing, Shao Na, Ma Sha, Shang Hui-Fang
Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China.
Clinical Diagnostic Department, Guangzhou KingMed Diagnostics Group Co. Ltd, Guangzhou, China.
Eur J Neurol. 2022 Nov;29(11):3218-3228. doi: 10.1111/ene.15509. Epub 2022 Aug 4.
Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese.
In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed.
Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction.
Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.
近期遗传学研究进展表明，许多与帕金森病（PD）相关的致病/风险基因主要存在于欧洲血统的患者中。本研究旨在调查与PD相关的基因，并确定中国汉族早发性PD的突变谱。
本研究对704例早发性PD（EOPD）患者（发病年龄≤45岁）和1866例对照进行了全外显子测序和/或基因剂量分析。分析了26个与PD相关的基因以及20个与神经退行性疾病和溶酶体疾病相关的其他基因。
共鉴定出82例（11.6%，82/704）EOPD患者在与PD相关的基因中携带罕见的致病/可能致病变异。常染色体隐性遗传EOPD的突变频率（42.9%，27/63）远高于常染色体显性遗传EOPD（0.9%，12/110）或散发性EOPD（8.1%，43/531）。PRKN基因的双等位基因突变最为常见，占EOPD病例的5.1%。三个常见的致病变异，即SNCA基因中的p.A53V、PRKN基因中的p.G284R和CHCHD2基因中的p.P53Afs38，仅在亚洲人中出现。来自GBA、PRKN、DJ1、PLA2G6和GCH1的推定有害变异导致了EOPD的总体风险。值得注意的是，CHCHD2基因中的蛋白质截短变异在EOPD中富集，尤其是p.P53Afs38，在一个独立的晚发性PD患者队列（n = 1300）的三名患者中也发现了该变异。功能实验证实，截短的CHCHD2变异导致功能丧失，并与线粒体功能障碍有关。
我们的研究揭示了中国汉族EOPD的遗传谱，这可能有助于制定基因扫描策略，为支持CHCHD2基因与PD的关系提供了更多证据。
