Oligogenic Pathogenesis Study Of Amyotrophic Lateral Sclerosis

Objective:1.To investigate all exomes of 20 known amyotrophic lateral sclerosis(ALS)-related genes in 311 sporadic ALS patients who were of Chinese ancestry using next-generation sequencing technology and the oligogenic pathogenesis of ALS on the basis of common disease rare variant hypothesis.2.To investigate the difference in rare variant frequency of ALS-related genes between Chinese and Europeans.Methods:1.Genomic DNA was extracted from whole blood of all 311 SALS patients using standard methods.DNA of all patients was screened for variants in all exons of ANG,ATXN2,CHMP2B,DAO,DCTN1,ELP3,FIG4,FUS,HNRNPA1,MATR3,NEFH,OPTN,PFN1,SETX,SIGMAR1,SOD1,SQSTM1,TARDBP,UBQLN2,and VAPB using next-generation sequencing technology.Known pathogenic and potentially pathogenic variants were identified by searching the databases.2.To compare rare variant frequency of ALS-related genes between Chinese and Europeans.3.To screen patients who carried two or more variants of 20 ALS-related genes.Results:1.Among the 33 kinds of variants that were reported in the ExAC database in our study,16 kinds of variants were reported in East Asians,no in Europeans,and a higher frequency was found in East Asians than in Europeans for the 11 kinds of variants.2.9(2.8%)patients harbored 2 or 3 variants of 17 ALS-related genes and might relate to oligogenic pathogenesis.Conclusion:1.The differences in the frequencies of the variants identified in 20 ALS-related genes could be responsible for the differences in age and site of symptom onset betweenChinese and European SALS patients.2.SALS patients could harbor two or more variants of known ALS-related genes.The phenotypic outcome might be determined by multiple genes.