Unveiling Digenic Pathogenic Variants and Mutation Susceptibility in Chinese Patients with Suspected Retinitis Pigmentosa

Abstract Background Retinitis pigmentosa (RP; MIM: #268000) is a type of inherited retinal dystrophy (IRD) characterized by the progressive loss of retinal photoreceptors. In recent years, the field of bioinformatics has made significant advancements, enabling us to uncover new digenic disease variants associated with RP. Additionally, there is increasing attention given to identifying prevalent founder mutations, as they have the potential to be targeted by mutation-specific therapies that focus on specific regions of the genome. Methods We conducted a retrospective study involving 450 patients who were diagnosed with suspected RP as the study cohort. To serve as a control cohort, we included their family members. In this study, we aimed to establish a genotype-phenotype correlation among all participants. For patients who did not have any identified pathogenic variants, we performed digenic pathogenicity prediction along with Sanger sequencing validation. Furthermore, we conducted transmission linkage disequilibrium analysis to identify susceptibility loci for all patients. Result In our study, we achieved a molecular diagnosis in 67.8% of the patients, with the top 17 genes accounting for 75.63% of the 305 diagnosed cases. We identified a total of 464 known pathogenic loci, consisting of 103 different variants, as well as 73 novel pathogenic loci with 43 different variants. Among these findings, we discovered 12 suspected pathogenic digenic loci pairs, and two of them were successfully validated through Sanger sequencing - PDE6A c.1744C > T/RP1 c.607G > T and CRB1 c.2714G > A/PROM1 c.1438G > A. After applying the Bonferroni correction, we identified eight significant mutations associated with suspected RP. These mutations include MSH2 c.212-16delT, LRP5 c.58-60del, FOXE3 c.211A > G, PRX c.4077-4079del, DMD c.8810A > A, GP1BA c.1322-1344del, SYNE2 c.1170A > C, and SMPD1 c.573T > C. Additionally, our study unveiled 26 combinations of highly correlated susceptible loci involving 31 genes. Among these combinations, MSH2 c.212-16delT and WFS1 c.1832G > A were identified as susceptible interaction hotspots. Conclusion In conclusion, this retrospective study demonstrated that a considerable number of patients achieved a molecular diagnosis. Furthermore, the study aimed to identify novel digenic disease variants in patients with suspected RP utilizing bioinformatics methods. The findings of the study also unveiled significant susceptible mutations associated with suspected RP, shedding light on potential targets for mutation-specific therapy in the future.