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Background and purpose: Haploinsufficiency of TANK‐binding kinase 1 (TBK1) loss‐of‐function (LoF) variants has been shown to be pathogenic in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the genetic spectrum of TBK1 and clinical features of ALS patients with TBK1 variants remain largely unknown in Asians. Methods: Genetic analysis was performed on 2011 Chinese ALS patients. Software was used to predict the deleteriousness of missense variants in TBK1. In addition, PubMed, Embase and Web of Science were searched for related literature. Results: Twenty‐six TBK1 variants were identified in 33 of 2011 ALS patients, including six novel LoF variants (0.3%) and 20 rare missense variants, 12 of which were predicted to be deleterious (0.6%). In addition to TBK1 variants, 11 patients had other ALS‐related gene variants. Forty‐two previous studies found that the frequency of TBK1 variants was 1.81% in ALS/FTD patients. The frequency of TBK1 LoF variants in ALS was 0.5% (Asians 0.4%; Caucasian 0.6%) and that of missense variants was 0.8% (Asians 1.0%; Caucasian 0.8%). ALS patients with TBK1 LoF variants affecting the kinase domain had a significantly younger age of onset than patients carrying LoF variants affecting the coiled coil domains CCD1 and CCD2. FTD has a frequency of 10% in Caucasian ALS patients with TBK1 LoF variants, which was not found in our cohort. Conclusion: Our study expanded the genotypic spectrum of ALS patients with TBK1 variants and found that the clinical manifestations of TBK1 carriers are diverse. [ABSTRACT FROM AUTHOR]

Study objectives: Recently, AOPEP has been identified to be a novel causative gene of autosomal-recessive dystonia. However, no large cohort study has been conducted to confirm the association. We aimed to systematically evaluate the genetic associations of AOPEP with dystonia in a large Chinese dystonia cohort. Methods: We analyzed rare variants of AOPEP in 878 dystonia patients with whole-exome sequencing. The over-representation of rare variants in patients was examined with Fisher's exact test at allele and gene levels. Results: Among the 878 patients with dystonia, we found two patients with biallelic likely pathogenic variants in the AOPEP gene. One patient carried putative compound heterozygous variants (p.A212D and p.G216R) and presented with childhood-onset segmental dystonia involving the upper limbs and craniocervical muscles accompanied by myoclonus of the dystonia affected areas. One patient carried homozygote of p.M291Nfs*68 and presented with adult-onset isolated cervical dystonia. Another 15 patients were identified to carry heterozygous rare variants in AOPEP, including 2 loss-of-function variants (p.M291Nfs*68 and p.R493X) and 6 missense variants. One loss-of-function variant (p.R493X) was the same as previously reported. Nearly, all of the 15 patients carrying heterozygous variants in AOPEP presented with isolated dystonia with only craniocervical muscles affected, except for one patient who carried the p.R493X variant presented with segmental dystonia affecting the neck and right upper limb combined with parkinsonism. Gene-based burden analysis detected enrichment of rare variants and rare damaging variants of AOPEP in dystonia. Conclusions: Our study supplemented the evidence on the role of AOPEP in autosomal-recessive dystonia in Chinese population, and expanded the genotypic and phenotypic spectrum of AOPEP. [ABSTRACT FROM AUTHOR]

Study objectives: Recently, IMPDH2 has been linked to dystonia. However, no replication study from other cohorts has been conducted to confirm the association. We aimed to systematically evaluate the genetic associations of IMPDH2 with dystonia in a large dystonia cohort. Methods: We analyzed rare variants (minor allele frequency < 0.01) of IMPDH2 in 688 Chinese dystonia patients with whole exome sequencing. The over-representation of rare variants in patients was examined with Fisher's exact test at allele and gene levels. Results: Four rare variants were detected in IMPDH2 in four patients with dystonia in our cohort, including three missense variants (p.Ser508Leu, p.Ala396Thr, and p.Phe24Val) and one splice acceptor variant (c.1296-1G>T). Two of them (c.1296-1G>T and p.Ser508Leu) were co-segregated in the family co-segregation analysis and were classified as pathogenic and likely pathogenic variant according to the American College of Medical Genetics and Genomics (ACMG) guidelines, respectively. Gene burden analysis revealed enrichment of rare variants in IMPDH2 in dystonia. Conclusions: Our work supplemented the evidence on the role of IMPDH2 in autosomal dominant dystonia in Chinese population, and expanded the genetic and phenotypic spectrum of IMPDH2, paving way for future studies. [ABSTRACT FROM AUTHOR]

Homozygous missense variants in PTRHD1 have been identified to cause parkinsonism by segregation analysis in families. Further replication in the Parkinson's disease (PD) population might provide additional insight. Here, we analyzed the rare variants in a Chinese PD cohort (Ncase = 1367, Ncontrol = 3298) with whole exome sequencing. We did not identify the variants described in previous studies, and no patient carried other homozygous or compound heterozygous variants of PTRHD1. Three rare variants were identified, but rare variants of PTRHD1 were not enriched in PD. Genetic screening suggested rare variants of PTRHD1 as disease cause were rare in PD in East Asians. [ABSTRACT FROM AUTHOR]

Background: The progression of motor and non-motor symptoms (NMS) and the sensitivity of each item of the Unified Multiple System Atrophy Rating Scale (UMSARS) to change remain unclear in Chinese patients with early-stage multiple system atrophy (MSA). We investigated the evolution of motor symptoms and NMS in early-stage MSA and the sensitivity of each item included in the UMSARS to change over a 2-year follow-up.Methods: Motor symptoms and NMS were recorded at baseline and at 1- and 2-year follow-ups based on the UMSARS and the NMS scale. Generalized estimating equation models were used. The sensitivity of an item included in the UMSARS to change was assessed by calculating a standardized effect using the mean annual change divided by the standard deviation of the change.Results: We enrolled 246 consecutive patients with MSA and 97 MSA completed the 2-year follow-up. The mean total UMSARS score increased by 11.90 and 22.54 points at the 1- and 2-year follow-ups, respectively. UMSARS-I items associated with motor functions were more sensitive to change and those associated with autonomic dysfunction showed less sensitivity to change. Items 4 (tremor at rest), 5 (action tremor), and 3 (ocular motor dysfunction) of the UMSARS-II were less sensitive to change. The prevalence and severity of NMS significantly increased over the 2-year follow-up.Conclusions: We observed significant progression in motor symptoms and NMS in patients with early-stage MSA. Our results provide useful information to support the revision of the UMSARS. [ABSTRACT FROM AUTHOR]

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis. Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%. Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS. Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed. [ABSTRACT FROM AUTHOR]

A loss-of-function variant in Lin-28 Homolog A gene (LIN28A p. R192G, rs558060339) has been identified in two East Asian ancestry patients with early-onset PD (EOPD). Functional studies revealed that such a variant could lead to developmental defects and PD-related phenotype, and the phenotypes could be rescued after correction of the variant. The aim of the study was to screen the variants of LIN28A in Chinese patients with EOPD. A total of 682 EOPD patients were sequenced with whole exome sequencing and the coding and flanking region of LIN28A were analyzed. We identified a rare coding variant, p. P182L, of LIN28A in a Chinese patient with EOPD. Moreover, we also found a 3′-UTR polymorphism (rs4659441) to be associated with an increased risk for PD. However, our rare variant burden analysis did not support a role for LIN28A as a major causal gene for PD. [ABSTRACT FROM AUTHOR]

Background: Abnormal eye movements are common in spinocerebellar ataxias Type 3 (SCA3). We conducted the research to explore the frequency of abnormal eye movements in Chinese patients with SCA3, to compare the demographic and clinical characteristics between SCA3 patients with and without each type of abnormal eye movement, and to explore the correlation between abnormal eye movements and the severity of ataxia.Methods: Seventy-four patients with SCA3 were enrolled in this cross-sectional study. Six types of abnormal eye movements including impaired smooth pursuit, increased square-wave jerks (SWJ), gaze-evoked nystagmus (GEN), slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy were evaluated by experienced neurologists. The severity of ataxia was evaluated by Scale for the Assessment and Rating of Ataxia (SARA).Results: The prevalence of impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy in Chinese SCA3 patients was 28.4, 13.5, 78.4, 41.9, 23.0, and 5.4%, respectively. SCA3 patients with GEN had higher scores of International Cooperative Ataxia Rating Scale (ICARS-IV) and total ICARS, and longer length of CAG repeat than patients without GEN. SCA3 patients with slowing of saccades had a longer disease duration, higher scores of ICARS-I, ICARS-II, total ICARS and SARA than patients without slowing of saccades. SCA3 patients with saccadic hypo/hypermetria had higher scores of ICARS-III, ICARS-IV, and SARA than patients without saccadic hypo/hypermetria. The demographic and clinical characteristics did not differ significantly between SCA3 patients with and without impaired smooth pursuit, increased SWJ, or supranuclear gaze palsy. Multivariate linear regression showed that the number of abnormal eye movements (0-6), disease duration, Hamilton Depression Rating Scale-24 (HDRS-24) score, and CAG repeat length were positively correlated with SARA score, whereas Montreal Cognitive Assessment (MoCA) score was negatively correlated with SARA score in SCA3.Conclusions: An increased number of abnormal eye movement types correlated with the severity of ataxia in SCA3. [ABSTRACT FROM AUTHOR]

A missense variant of uncertain significance in a Chinese patient with segmental dystonia (cranial-cervical dystonia) was also reported.3 In the current study, we identified 1 likely pathogenic de novo rare missense variant in a Chinese patient with childhood-onset generalized dystonia with myoclonus, which has been rarely reported previously. Dystonia is a syndrome consisting of sustained or intermittent contraction of muscle that leads to abnormal movements or postures. [Extracted from the article]

Introduction: Amounting evidence has suggested the Tripartite Motif (TRIM) family proteins as related to Parkinson's disease (PD). However, many of the risk genes were still awaiting further explorations, and their genetic role in PD has not been investigated yet.Methods: Here, we aimed to systematically evaluate the genetic associations of TRIMs with PD in a large Chinese early-onset PD (EOPD, age at onset < 50 years) cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated EOPD patients using whole exome sequencing, and evaluated the association between rare variants and EOPD at allele and gene levels.Results: Totally 123 rare variants were identified in 13 TRIM protein family members, including TRIM3, TRIM6, TRIM8, TRIM9, TRIM10, TRIM11, TRIM17, TRIM24, TRIM27, TRIM28, TRIM34, TRIM40 and TRIM41. At the allele level, three variants were nominally associated with PD, namely p.R65H in TRIM10, p.P467S in TRIM11, and p.I425V in TRIM24. Gene-based burden analysis showed a clear enrichment of rare variants of TRIM24 in EOPD.Conclusion: These results demonstrate TRIM24 as a potential risk gene for PD, provide a better understanding for the genetic involvement of TRIM protein family members in EOPD and broaden the current mutation spectrum of PD. [ABSTRACT FROM AUTHOR]

• Mutation analysis for GWAS-linked SLCs in a large Chinese early-onset PD cohort. • Six mutations were identified as nominally associated with early-onset PD. • Burden test supports the role of SLC2A13 mutations in early-onset PD. The solute carrier (SLC) transporters have been suggested to play important roles in neurodegenerative disorders. Recently, seven SLC transporters were identified to be associated with Parkinson's disease (PD) by genome-wide association studies. However, few replications were conducted, and whether rare variants in these genes were associated with PD was not explored yet. To elucidate the genetic associations of these SLCs with PD, we investigated the rare variants in 743 Chinese early-onset PD (EOPD) patients using whole-exome sequencing, and evaluated the association between rare variants and PD at allele and gene levels. Totally, 58 rare variants were identified in SLC50A1, SLC41A1, SLC45A3, SLC44A4, SLC56A2, SLC2A13 and SLC38A1. At allele level, 6 variants were nominally associated with PD, namely p.S423G in SLC45A3 , p.I551V, p.T435S, p.R323C and p.V101M in SLC2A13 , and p.R285Q in SLC41A1. Gene-based burden analysis showed enrichment of rare variants of SLC2A13 in EOPD. Our study systematically analyzed the genetic involvement of SLCs in EOPD, identified SLC2A13 as a risk gene for PD, and broadened the current mutation spectrum of PD. [ABSTRACT FROM AUTHOR]

Members of the transmembrane (TMEM) protein family have been identified to be associated with Parkinson's disease (PD) and other neurodegenerative disorders. However, most studies were based on the European-ancestry population and were still awaiting replications. Here, we aimed to systematically evaluate the associations of TMEMs with PD in a large Chinese early-onset PD (EOPD, age at onset <50 years) cohort. We identified rare variants (minor allele frequency <0.01) in 743 unrelated EOPD patients using whole-exome sequencing and evaluated the association between variants and EOPD at allele and gene levels. Totally 45 rare variants were identified in 6 TMEM protein family members. At allele level, p.176 K>E in TMEM175 and p.33P>R in TMEM163 were significantly associated with PD. Gene-based burden analysis showed a clear enrichment of TMEM163 variants in EOPD. Our work identifies 2 novel rare variants and TMEM163 as potential risk factors for PD provide a better understanding of the genetic involvement of TMEM protein family members in EOPD and broadens the current mutation spectrum of PD. • TMEM family members mutation analysis in a large Chinese early-onset PD cohort. • Two significant variants in TMEM175 and TMEM163 were identified. • Burden test supports the role of TMEM163 variants in early-onset PD. [ABSTRACT FROM AUTHOR]

The glycosyltransferase 8 domain containing 1 (GLT8D1) gene was identified to be an amyotrophic lateral sclerosis (ALS)-causative gene via pedigree cosegregation and burden analysis. In the present study, 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases underwent whole-exome sequencing. Rare variants with minor allele frequency <0.1% in GLT8D1 were analyzed. One likely pathogenic variant in the exon 4 was identified in a fALS case and validated within the family. Moreover, 3 rare variants of uncertain significance in 4 patients with sALS and 1 rare variant of uncertain significance in 1 patient with fALS were also identified. Furthermore, by using the East Asian controls from the gnomAD database, there was no significant enrichment of rare variants of GLT8D1 at the whole-gene level or the exon 4–specific level in Chinese patients with sALS. In conclusion, cosegregation findings further support the pathogenic role of GLT8D1 in fALS. However, no pathogenic mutation and no enrichment of rare variants were found in patients with sALS, which implies that GLT8D1 may not play a role in Chinese patients with sALS. • We screened GLT8D1 in a large cohort of ALS patients via whole exome sequencing. • Co-segregation of the p.G78 A variant confirms GLT8D1 as a familial ALS gene. • No pathogenic variant and no enrichment of variants were found in sporadic ALS. [ABSTRACT FROM AUTHOR]

Recently, LRP10 has been identified as a causative gene for Parkinson's disease (PD). However, subsequent studies showed inconsistent conclusions. To explore its relevance to PD, we systematically analyzed LRP10 rare mutations in a large Han Chinese familial PD cohort of 385 unrelated probands using segregation analysis, transcriptional effect analysis, and burden test. As a result, 3 missense variants and 1 splicing region variant in LRP10 were identified in 4 probands. Segregation analysis revealed 1 variant p.Arg66His cosegregating with PD status, 1 variant p.Ala613Ser not, and the other variant p.Gln581His unknown. The variant c.406+5G>T located at the splicing region has no effect on splicing, suggesting it is likely a rare neutral intronic variant. The burden test suggested no significant over-representation of rare variants in PD probands. Therefore, more robust independent studies are warranted to explore the pathogenicity of LRP10 mutations. • LRP10 mutation analysis in a large Han Chinese familial PD cohort. • Four novel rare variants in LRP10 were identified. • In this study, burden test does not support the pathogenicity of LRP10 variants for PD. [ABSTRACT FROM AUTHOR]

Homozygous and compound heterozygous mutations in the vacuolar protein sorting 13C (VPS13C) gene can cause autosomal recessive parkinsonism via mitochondrial pathway. The present study aimed to screen the mutations of VPS13C in a cohort of Chinese patients with early-onset Parkinson's disease (EOPD) and further explore its pathogenicity via burden analysis. A total of 669 patients with EOPD were sequenced with whole-exome sequencing and analyzed homozygous or compound heterozygous mutations in VPS13C. Moreover, rare variants with minor allele frequency <0.1% were included in the burden analysis. In total, 7 (1.05%) patients with EOPD carried compound heterozygous mutations in VPS13C , including 3 patients with novel compound heterozygous missense mutations and 4 patients with at least 1 nonsense or splicing-site mutations. Furthermore, burden analysis indicated that patients with EOPD had an enrichment of rare variants in VPS13C. In conclusion, our findings of compound missense mutations expanded the mutation spectrum of VPS13C in EOPD. Burden analysis further elucidated the importance of VPS13C in the pathogenesis of PD. • The first study on the mutation screening of VPS13C in Chinese patients with EOPD. • Expanded the mutation spectrum of VPS13C by identifying 3 patients with novel pure compound missense mutations. • Burden analysis indicated that patients with EOPD had an enrichment of rare variants in VPS13C. [ABSTRACT FROM AUTHOR]