Background: Defects in the α-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 α-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 α-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 α-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 α-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 α-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 α-synuclein variants showed both rapid progression and worse cognitive impairment.
Conclusion: Our study provides a better understanding of the clinical and genetic correlations of α-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. © 2020 International Parkinson and Movement Disorder Society.
Keywords: burden analysis; early-onset Parkinson's disease; genetic; next-generation sequencing; rare variants.
© 2020 International Parkinson and Movement Disorder Society.