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Objective To identify causative genetic mutations by targeted exome sequencing in 9 independent pedigrees with familial exudative vitreoretinopathy (FEVR) and characterize the novel pathogenic mutations by molecular dynamics simulation. Methods Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by the Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, Mutation taster, and GERP++) were carried out to evaluate the pathogenicity of the mutations. Molecular dynamics was simulated to predict the alterations of protein conformation and flexibility transformation on pathogenesis. Results A 44% overall detection rate was achieved with four mutations including c.4289delC:p.Pro1431Argfs*8, c.2073G > T:p.Trp691Cys, c.1801G > A:p.Gly601Arg in LRP5 and c.633T > A:p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC:p.Pro1431Argfs*8 and c.2073G > T:p.Trp691Cys of LRP5 were identified as novel pathogenic mutations. According to a molecular dynamics simulation, both mutations altered the secondary structure and spatial conformation, thus compromising its stability and flexibility. Conclusion Two novel genetic variants of the LRP5 gene were found to contribute to FEVR in this study, enriching the mutation spectrum of this condition. The impact of these two mutations on protein structure was validated by molecular dynamics simulation, further evidencing their pathogenicity.