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Benign familial infantile seizures (BFIS) is an autosomal dominant epileptic syndrome characterized by afebrile partial seizures with or without secondary generalized tonic-clonic seizures beginning at three to ten months of age. Genetic studies have revealed three susceptibility chromosomal loci on 19q12-q13.1, 16p12-q12 and 2q24. Previously we described the novel locus on 1p36.12-p35.1 for a Chinese family affected with BFIS, and below is a subsequent mutation analysis of candidate genes for the mapped chromosome region. Forty-five genes were selected and subjected to mutation analysis. Thirty-six nucleotide variants were found, none of which led to pathogenic changes, thereby were identified as nucleotide polymorphisms. The analyses suggest those candidate genes that were detected might not be involved in the epileptogenesis of pure BFIS, at least in the Chinese family we studied.

Background: The expression pattern represents a quantitative phenotype that provides an in-depth view of the molecular mechanism in Parkinson's disease (PD); however, the expression patterns of PD-associated genes (PAGs) and their relation to age at onset (AAO) remain unclear. Methods: The known PD-causing genes and PD-risk genes, which were collected from latest published authoritative meta-analysis, were integrated as PAGs. The expression data from Genotype-Tissue Expression database, Allen Brian Map database, and BrainSpan database, were extracted to characterize the tissue specificity, inhibitory-excitatory neuron expression profile, and spatio-temporal expression pattern of PAGs, respectively. The AAO information of PD-causing gene was download from Gene4PD and MDSgene database. Results: We prioritized 107 PAGs and found that the PAGs were more likely to be expressed in brain-related tissues than non-brain tissues and that more PAGs had higher expression levels in excitatory neurons than inhibitory neurons. In addition, we identified two spatio-temporal expression modules of PAGs in human brain: the first module showed a higher expression level in the adult period than in the prenatal period, and the second module showed the opposite features. It showed that more PAGs belong to the first module that the second module. Furthermore, we found that the median AAO of patients with mutations in PD-causing genes of the first module was lower than that of the second module. Conclusion: In conclusion, this study provided comprehensive landscape of expression patterns, AAO features and their relationship for the first time, improving the understanding of pathogenesis, and precision medicine in PD. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. A significant overlap in clinical features, epidemiology, imaging, and pathology suggests that PD and ET may also share common genetic risk factors. Previous studies have only assessed a limited number of ET‐associated genes in PD patients and vice versa. Consequently, the genetic association between PD and ET remains incompletely characterized. In this study, we systematically investigated a potential association between rare coding variants in ET‐associated genes and PD, in a relatively large Chinese population cohort. Methods: To investigate the genetic association between ET and PD, we performed the sequence kernel association testing (SKAT‐O) to explore the variant burden of 33 ET‐associated genes, using whole‐exome sequencing (WES) data from 1494 early‐onset PD (EOPD) patients and 1357 control subjects from mainland China. Results: We report that rare loss‐of‐function and damaging missense variants of TNEM4 are suggestively associated with EOPD (P = 0.026), damaging missense variants of TNEM4 alone are also suggestively associated with EOPD (P = 0.032). No other rare damaging variants in ET‐related genes were significantly associated with EOPD. Interpretation: This is the first systematic analysis of ET‐associated genes in EOPD. The suggestive association between TNEM4 and EOPD provides new evidence for a genetic link between ET and PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disease with inherent sex differences, and sex-determining region Y (SRY) is a gene located in the Y chromosome which encodes a transcription factor involving the regulation of the dopamine system. In this study, we investigated whether SRY variants were associated with PD in Chinese population. A total of 2058 male patients with PD and 1650 male control participants were recruited, and variants in SRY transcript and flanking regions were genotyped by whole-exome sequencing or whole-genome sequencing. Analysis of rare variants by the optimal sequence kernel association test showed no difference in variant burden of coding, 5′-noncoding and 3′-noncoding between the case and control group. In addition, of the 6 common variants identified, none showed a significant effect in altering PD risk in our population using logistic regression. Our results suggested SRY variants were not associated with the risk of PD in Chinese population. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disease with a relatively unclear etiology. Previous studies have shown that N6-methyladenosine (m6A) is a vital RNA modification enriched in brain tissue, and that the genes involved in m6A modification are implicated in various neurologic diseases. Here, we conducted a comprehensive genetic analysis using targeted sequencing with molecular inversion probes (MIPs) to identify m6A-modification genes (including METTL3, METTL14, WTAP, FTO, ALKBH5, YTHDF1, YTHDF2, YTHDF3, HNRNPC, and ELAVL1) in a total of 1647 sporadic PD patients and 1372 controls of Han Chinese origin. PD patients were divided into early-onset PD (EOPD) and late-onset PD (LOPD) based on whether the onset of motor symptoms occurred before or after 50 years of age. Rare variants were subjected to gene-based burden tests and common variants were subjected to single-variant association analyses. As a result, we identified 214 rare variants in all 10 m6A-modification genes and 16 common variants in 7 genes. Gene-wise association analyses of rare variants in each m6A-modification gene did not achieved a p value of less than 0.05 in either total cohorts or 2 age groups. In fact, p values greater than 0.05 were found when conducting single-variant association analyses on common variants of these genes between PD and control patients. Our comprehensive analyses of m6A-modification genes suggest that there is no significant association between these 10 m6A-modification genes and the risk of sporadic PD. • A relatively large cohort of Chinese PD patients and controls were included. • A comprehensive analysis on the 10 m6A genes in PD and controls using MIPs. • No significant association between these 10 m6A genes and the risk of sporadic PD. [ABSTRACT FROM AUTHOR]

DNA methylation is an important regulatory mechanism of Parkinson's disease (PD). To investigate the relationship between DNA methylation and hydroxymethylation genes and PD, we performed gene-targeted sequencing using molecular inversion probes in a Chinese PD population. We sequenced 12 genes related to DNA methylation and hydroxymethylation in 1657 patients and 1394 control subjects. We conducted genewise association analyses of rare variants detected in the present study and identified the TET1 gene as important in PD (p = 0.0037738, 0.013, 0.019521 (b.collapse test, variable threshold test, and skat-o test, respectively; sex + age as covariates). However, no positive results were observed when conducting association analyses on common variants in these genes. We performed a comprehensive analysis of associations between variants of DNA methylation and hydroxymethylation genes and PD, resulting in determination that TET1 might play a role in PD. • A large Chinese PD cohort (1657 patients and 1394 controls) were included. • A comprehensive analysis on the 12 DNA methylation/hydroxymethylation genes in PD with target sequencing using molecular inversion probes (MIPs). • TET1 might play a role in PD. [ABSTRACT FROM AUTHOR]

Abstract Studies have shown that rare variants of Mendelian genes for Parkinson's disease (PD) contribute to sporadic PD in the Caucasian population, which lacked confirmation in the Chinese population. Because the autosomal-dominant PD (AD-PD) had a phenotype closely resembling sporadic PD, we performed a systematic analysis of 7 AD-PD genes (SNCA , LRRK2 , GIGYF2 , VPS35 , EIF4G1 , DNAJC13 , and CHCHD2) in 1456 Chinese sporadic PD patients and 1568 controls. Overall, 72 rare variants were identified, 7 of which were classified as likely pathogenic, 63 of which were categorized as of uncertain significance, and 2 of them were predicted to be likely benign. These AD-PD genes represented a clear enrichment of rare variants in PD patients from a burden analysis (p = 0.003), and significant differences could still be observed when likely pathogenic variants were removed (p = 0.027). The gene-based association testing also reached significance for LRRK2 (p = 0.004) and remained statistically significant after the Bonferroni correction. This report suggested that rare variants of AD-PD genes had a role in the Chinese sporadic PD cohort, especially for those rare variants of LRRK2. Highlights • Systematically screen autosomal-dominant genes in a sporadic PD cohort. • 72 rare variants were identified, 7 variants were classified as likely pathogenic. • A clear enrichment of total rare variants was observed in PD patients. • The gene-based association testing reached significance for LRRK2. [ABSTRACT FROM AUTHOR]