Whole Exome Sequencing Identifying Rare Pathogenic Genes In Chinese Sporadic Parkinson's Disease

Background: Parkinson's Disease(PD)is a common neurodegenerative disease.At present,the etiology and pathogenesis of the disease are not fully explained.Most scholars believe that the occurrence of PD is the result of genetic and environmental factors,and genetic factors play an important role.With the rapid development of gene sequencing technology,Whole Exome Sequencing(WES),which has the characteristics of short time-consuming,low cost,large throughput,and small sample size requirements,has become the current hot method of researching disease inheritance.By using WES,scholars can explore rare mutations in complex diseases,thus providing a genetic basis for early molecular diagnosis,prevention,and even treatment of complex disease.Objective: Based on the 2015 American College of Medical Genetics and Genomics(ACMG)guidelines,this study aims to use WES technology to explore rare mutation genes in the Chinese sporadic PD exome region and to make pathogenic annotations.Methods: 98 patients with sporadic PD were enrolled in the WES study.The rare mutant genes of exome region were filtered according to the public databases 1000 Genomes,gnom AD_exome,esp6500 and Ex AC,and the mutation pathogenicities were annotated with the public databases Clinvar,inter Var,dpsi,db NSFP and HGMD.Results: A total of 14 PD patients were found to have rare suspected pathogenic mutations in the exome region and 7 locus mutations of 6 genes were filtered,including 6 missense mutations and 1 frameshift mutation.?9 PD patients carry the LRRK2 gene c.7153G>A:p.G2385 R heterozygous mutation;2 PD patients carry the LRRK2 gene c.2264C>T:p.P755 L heterozygous mutation;1 PD patient carries the PINK1 gene c.1220G>A: p.R407 Q heterozygous mutation;1 PD patient carries TRPM7 gene c.3337 dup T: p.Y1113Lfs*12 frameshift mutation;1 PD patient carries DNAJC13 gene c.6227G>A:p.R2076 Q heterozygous mutation;1 PD patient carries the SNCA gene c.158C>T:p.A53 V heterozygous mutation;1 PD patient carries the GBA gene c.1448T>C:p.L483 P heterozygous mutation.?In the Clinvar database,the GBA mutant L483 P was annotated as“Likely to be pathogenic”,while the LRRK2 mutants G2385 R and P755 L were annotated as “Other”;In the inter Var database,the GBA mutant L483 P was annotated as “Likely pathogenic”,while LRRK2 mutants G2385 R and P755 L,PINK1 mutant R407 Q,DNAJC13 mutant R2076 Q,SNCA mutant A53 V were all annotated as “Uncertain significance”;In dpsi database,the DNAJC13 mutant R2076Q and the SNCA mutant A53 V were annotated as highly pathogenic(High),the LRRK2 mutant G2385 R was annotated as moderately pathogenic(Media),the GBA mutant L483 P,the LRRK2 mutant P755 L and the PINK1 mutant R407 Q were annotated as low pathogenicity(Low);In the database db NSFP,DNAJC13 mutant R2076 Q,SNCA mutant A53 V and PINK1 mutant R407Q were all annotated as disease-causing mutation(DM).LRRK2 mutants G2385R and P755 L,GBA L483 P mutant were all annotated as suspected pathogenicity(DM);In the HGMD database,the GBA mutant L483 P and the PINK1 mutant R407 Q were annotated as pathogenicity(DM),and the LRRK2 mutant G2385 R was annotated as disease-associated polymorphism with additional functional evidence(DFP),the LRRK2 mutant P755 L was annotated as disease-associated polymorphism(DP).The TRPM7 frameshift mutant Y1113Lfs*12 was not found in these databases.Conclusion: Our study found TRPM7 gene c.3337 dup T:p.Y1113Lfs*12frameshift mutation in PD patients firstly,which may have a inherited effect on the explaination of PD pathogenesis.Our study also confirmed the significance of LRRK2 mutant G2385 R in PD pathogenesis in Asian population.In addition,our study provided bioinformation for exploring the relationship between PINK1,DNAJC13,GBA,LRRK2,SNCA mutations and PD pathogenesis.