Whole Exome Sequencing Analysis On Chinese Juvenile-onset Primary Open-angle Glaucoma Patients

Purpose:Our previous whole exome sequencing analysis on juvenile-onset primary open-angle glaucoma（POAG）（JOAG）patients revealed only very few JOAG patients carrying the reported POAG gene mutations.In these years,genome-wide association studies（GWAS）have identified multiple genetic loci associated with POAG.Herein we hypothesized that JOAG patients could carry rare coding variants of the POAG-associated genes.In this study,we aimed to delineate the rare coding variants of the POAG-associated genes in the JOAG patients by whole exome sequencing analysis.Methods:Total 287 genes(p≤5×10^-8)were retrieved from the reported POAG-related GWAS publications from 2009 to 2019.Rare coding variants in these GWAS-associated genes were determined from whole exome sequencing analysis in58 sporadic JOAG patients（11-35 years old at diagnosis,male to female ratio 21:8）and 15 controls subjects（28-82 years old,male to female ratio 7:8）.Result:Total 662 rare coding variants were identified from 190 POAG-associated genes among 58 JOAG patients,whereas 166 rare coding variants were found in 91POAG-associated genes among 15 control subjects.With the comparison between the two groups,564 JOAG-specific rare coding variants in 190 POAG-associated genes were resulted.Moreover,with the prediction on the potential damaging effects by the SIFT,Polyphen2,Mutation Taster and CADD software,310 rare coding variants in145 POAG-associated genes were determined.In addition,by controlling the read depth（DP>20）,221 rare coding variants in 116 POAG-associated genes were finally identified.FLNB,TNS1,AKAP13,LRRK1 and PKHD1 were found to have higher frequencies of rare coding variants in patients,and they are associated with extracellular matrix,focal adhesion and Wnt signaling pathways.Conclusions:In summary,results from this study revealed the rare coding variants of POAG-associated genes carried by JOAG patients.The POAG-associated rare coding variants could potentially be the disease-causing mutations among these JOAG patients.The genes of rare coding variants are mainly associated with extracellular matrix,focal adhesion and Wnt signaling pathways.This study would help to understand the molecular etiology and pathological mechanisms of POAG patients and provide new disease-associated genes for risk assessment and genetic diagnosis among JOAG patients in China and Asia.