期刊
MOVEMENT DISORDERS
卷 35, 期 11, 页码 2046-2055出版社
WILEY
DOI: 10.1002/mds.28191
关键词
burden analysis; early-onset Parkinson's disease; genetic; next-generation sequencing; rare variants
资金
- National Key Research and Development Program of China [2016YFC0901504, 2018YFC1312001]
- National Natural Science Fund of China [81571247]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYJC18038, ZYJC18003]
Background Defects in the alpha-synuclein, leucine-rich repeat kinase 2, or glucocerebrosidase genes have been regarded as essential contributors to PD. However, genetic variability of these genes with respect to early-onset PD remains poorly defined for the Chinese demographic. Objectives We aim to systematically characterize the clinical and genetic architecture of alpha-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in Chinese early-onset PD patients. Methods Whole-exome sequencing and Sanger sequencing were used to identify variants of alpha-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in 662 Chinese early-onset PD patients. Haplotype and burden analyses were conducted to investigate the role of rare variants of these three genes in early-onset PD. Results Sixty rare variants, including 23 novel variants, were identified in 73 patients (11.0%). Frequencies of patients with rare pathogenic/likely pathogenic variants of alpha-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase were 0.6%, 3.0%, and 5.4%, respectively. Evidences of two founder events exclusive to Asians were identified in 2 patients with leucine-rich repeat kinase 2 p.R1441C and 3 patients with alpha-synuclein p.A53V. Gene-based burden analysis supported glucocerebrosidase as a strong risk factor for early-onset PD, but argued against over-representation of rare variants in alpha-synuclein or leucine-rich repeat kinase 2 in early-onset PD. Clinically, no differences in motor or nonmotor symptoms were found between glucocerebrosidase variants carriers, and noncarriers or between leucine-rich repeat kinase 2 carriers and noncarriers. Patients with alpha-synuclein variants showed both rapid progression and worse cognitive impairment. Conclusion Our study provides a better understanding of the clinical and genetic correlations of alpha-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in early-onset PD, which may be beneficial for drafting genetic scanning strategies and evaluating disease progression. (c) 2020 International Parkinson and Movement Disorder Society
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