Abstract 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.

Background: Numerous studies have indicated that there is a possible relationship between GBA variants and Parkinson's disease (PD), however, most of them focused on a few variants such as L444P, N370S. We performed a comprehensive pooled analysis to clarify the relationship between variations of GBA and the risk of PD in different racial groups.Methods: Standard meta-analysis was conducted, including generating inclusion and exclusion criteria, searching literature, extracting and analyzing data.Results: Fifty studies containing 20,267 PD patients and 24,807 controls were included. We found that variants 84insGG, IVS2+1G>A, R120W, H255Q, E326K, T369M, N370S, D409H, L444P, R496H and RecNciI increased the risk of PD in total populations (OR: 1.78–10.49; p: <0.00001, 0.00005, 0.0008, 0.005, <0.00001, 0.004, <0.00001, 0.0003, <0.00001, <0.0001, 0.0001). In subgroup analysis by ethnicity, in AJ populations, variants 84insGG, R496H, N370S increased the risk of PD (OR: 9.26–3.51; p: <0.00001, <0.0001, <0.00001). In total non-AJ populations, variants L444P, R120W, IVS2+1G>A, H255Q, N370S, D409H, RecNciI, E326K, T369M increased the risk of PD (OR: 8.66–1.89; p: <0.00001, 0.0008, 0.02, 0.005, <0.00001, 0.001, 0.0001, <0.00001, 0.002). Among the non-AJ populations, pooled analysis from five different groups were done separately. Variants L444P, N370S, H255Q, D409H, RecNciI, E326K increased risk of PD (OR: 6.52–1.84; p: <0.00001, <0.00001, 0.005, 0.005, 0.04, <0.00001) in European/West Asians while R120W and RecNciI in East Asians (OR: 14.93, 3.56; p: 0.001, 0.003). L444P increased the risk of PD in Hispanics, East Asians and Mixed populations (OR: 15.44, 12.43, 7.33; p: 0.00004, <0.00001, 0.009). Lacking of enough original studies, we failed to conduct quantitative analysis in Africa.Conclusions: Obvious racial differences were found for GBA variants in PD. 84insGG and R496H exclusively increased PD risks in AJ populations, so did L444P, R120W, IVS2+1G>A, H255Q, D409H, RecNciI, E326K, T369M in non-AJ populations. N370S increased the risk of PD in both ethnics. In non-AJ subgroup populations, N370S, H255Q, D409H, E326K exclusively increased PD risks in European/West Asians, as were R120W in East Asians. L444P increased the risk of PD in all groups in non-AJ ethnicity. These results will contribute to the future genetic screening of GBA gene in PD.

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Background GBA gene had been proved to be a crucial gene to the risk of PD. Numerous studies had discussed about the unique clinical characteristics of PD patients with GBA carriers (GBA + PD). However, there was lack of updated comprehensive analysis on the topic. In order to clarify the association between GBA variants and the clinical phenotypes of PD, we conducted this comprehensive meta-analysis. Method Medline, Embase, and Cochrane were used to perform the searching. Strict selection criteria were followed in screening for new published articles or data. Revman 5.3 software was applied to perform the total statistical analysis, and funnel plots in the software were used to assess the publication biases. Results A total of 26 articles including 931 GBA + PD and 14861 GBA noncarriers of PD (GBA − PD) were involved in the final meta-analysis, and 14 of them were either newly added publications or related data newly analyzed compared with the version published in 2015. Then, a series of symptoms containing depression, orthostatic hypotension, motor fluctuation, wearing-off, and freezing were newly analyzed due to more articles eligible. Besides, clinical features like family history, AAO, UPDRS-III, H-Y, and dementia previously analyzed were updated with new data added. Significant statistical differences were found in wearing-off, family history, AAO, UPDRS-III, and dementia (OR: 1.14, 1.65; MD: −3.61, 2.17; OR: 2.44; p: 0.03, <0.00001, <0.00001, 0.003, and <0.00001). Depression was slightly associated with GBA + PD (OR: 1.47; p: 0.04). Clinical symptoms such as H-Y, orthostatic hypotension, motor fluctuation, and freezing did not feature GBA + PD. Conclusion Our results demonstrated that there were unique clinical features in GBA + PD which can help the management of the whole duration of PD patients.

Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Variants in the LRRK2 gene have been shown to be associated with PD. However, the clinical characteristics of LRRK2-related PD are heterogeneous. In our study, we performed a comprehensive pooled analysis of the association between specific LRRK2 variants and clinical features of PD.Methods: Articles from the Medline, Embase, and Cochrane databases were included in the meta-analysis. Strict inclusion criteria were applied, and detailed information was extracted from the final original articles included. Revman 5.3 software was used for publication biases and pooled and sensitivity analyses.Results: In all, 66 studies having the clinical manifestations of PD patients with G2019S, G2385R, R1628P, and R1441G were included for the final analysis. The prominent clinical features of LRRK2-G2019S-related PD patients were female sex, higher rates of early-onset PD (EOPD), and family history (OR: 0.77 [male], 1.37, 2.62; p < 0.00001, 0.02, < 0.00001). PD patients with G2019S were more likely to have high scores of Schwab & England (MD: 1.49; p < 0.00001), low GDS scores, high UPSIT scores (MD: 0.43, 4.70; p = 0.01, < 0.00001), and good response to L-dopa (OR: 2.33; p < 0.0001). Further, G2019S carriers had higher LEDD (MD: 115.20; p < 0.00001) and were more likely to develop motor complications, such as dyskinesia and motor fluctuations (OR: 2.18, 2.02; p < 0.00001, 0.04) than non-carriers. G2385R carriers were more likely to have family history (OR: 2.10; p = 0.007) than non-G2385R carriers and lower H-Y and higher MMSE scores (MD: −0.13, 1.02; p = 0.02, 0.0007). G2385R carriers had higher LEDD and tended to develop motor complications, such as motor fluctuations (MD: 53.22, OR: 3.17; p = 0.01, < 0.00001) than non-carriers. Other clinical presentations did not feature G2019S or G2385R. We observed no distinct clinical features for R1628P or R1441G. Our subgroup analyses in different ethnic group for specific variant also presented with relevant clinical characteristics of PD patients.Conclusions: Clinical heterogeneity was observed among LRRK2-associated PD in different variants in total and in different ethnic groups, especially for G2019S and G2385R.