The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.,Brain

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The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.
Brain ( IF 14.5 ) Pub Date : 2020-07-02 , DOI: 10.1093/brain/awaa167
Yuwen Zhao _{1,

2} , Lixia Qin _{1,

2} , Hongxu Pan ₁ , Zhenhua Liu _{1,

2} , Li Jiang ₁ , Yan He ₁ , Qian Zeng ₁ , Xun Zhou ₁ , Xiaoxia Zhou ₁ , Yangjie Zhou ₁ , Zhenghuan Fang ₃ , Zheng Wang ₄ , Yaqin Xiang ₁ , Honglan Yang ₁ , Yige Wang ₁ , Kailin Zhang ₁ , Rui Zhang ₁ , Runcheng He ₁ , Xiaoting Zhou ₁ , Zhou Zhou ₁ , Nannan Yang ₁ , Dongxiao Liang ₁ , Juan Chen ₁ , Xuxiang Zhang ₁ , Yao Zhou ₁ , Hongli Liu ₁ , Penghui Deng ₁ , Kun Xu ₁ , Ke Xu ₁ , Chaojun Zhou ₁ , Junfei Zhong ₁ , Qian Xu ₁ , Qiying Sun ₄ , Bin Li ₂ , Guihu Zhao ₂ , Tao Wang ₅ , Ling Chen ₆ , Huifang Shang ₇ , Weiguo Liu ₈ , Piu Chan _{9,

10} , Zheng Xue ₁₁ , Qing Wang ₁₂ , Li Guo ₁₃ , Xuejing Wang ₁₄ , Changshui Xu ₁₅ , Zhentao Zhang ₁₆ , Tao Chen ₁₇ , Lifang Lei ₁₈ , Hainan Zhang ₁₉ , Chunyu Wang ₁₉ , Jieqiong Tan ₃ , Xinxiang Yan ₂ , Lu Shen _{1,

2} , Hong Jiang _{1,

2} , Zhuohua Zhang ₃ , Zhengmao Hu ₃ , Kun Xia ₃ , Zhenyu Yue ₂₀ , Jinchen Li _{1,

2,

3,

4} , Jifeng Guo _{1,

2,

3} , Beisha Tang _{1,

2,

3,

4}

Affiliation

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China.
Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Department of Neurology, Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China.
Parkinson's Disease Center, Beijing Institute for Brain Disorders, Beijing 100101, China.
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, China.
Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450047, China.
Department of Neurology, Henan provincial people's hospital, Zhengzhou, Henan 450003, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Department of Neurology, Hainan General Hospital, Haikou, Hainan 570311, China.
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

This study aimed to determine the mutational spectrum of familial Parkinson’s disease and sporadic early-onset Parkinson’s disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson’s disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson’s disease, 242 probands from families with autosomal-dominant Parkinson’s disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson’s disease-associated genes occurred more frequently in the autosomal-recessive Parkinson’s disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson’s disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson’s disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson’s disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson’s disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson’s disease-associated genes. Our data highlight the importance of genetic testing in Parkinson’s disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

更新日期：2020-07-16

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