Landscape of pathogenic variants in six pre‐mRNA processing factor genes for retinitis pigmentosa based on large in‐house data sets and database comparisons

Purpose Variants in six genes encoding pre-mRNA processing factors (PRPFs) are a common cause of autosomal dominant retinitis pigmentosa (ADRP). This study aims to determine the characteristics of potential pathogenic variants (PPVs) in the six genes. Methods Variants in six PRPF genes were identified from in-house exome sequencing data. PPVs were identified based on comparative bioinformatics analysis, clinical phenotypes and the ACMG/AMP guidelines. The features of PPVs were revealed by comparative analysis of in-house data set, gnomAD and previously published literature. Results Totally, 36 heterozygous PPVs, including 19 novels, were detected from 45 families, which contributed to 4.4% (45/1019) of RP cases. These PPVs were distributed in PRPF31 (17/45, 37.8%), SNRNP200 (12/45, 26.7%), PRPF8 (10/45, 22.2%) and PRPF3 (6/45, 13.3%) but not in PRPF6 or PRPF4. Different types of PPVs were predominant in different PRPF genes, such as loss-of-function variants in PRPF31 and missense variants in the five remaining genes. The clustering of PPVs in specific regions was observed in SNRNP200, PRPF8 and PRPF3. The pathogenicity for certain classes of variants in these genes, such as loss-of-function variants in PRPF6 and missense variants in PRPF31 and PRPF4, requires careful consideration and further validation. The predominant fundus changes were early macular involvement, widespread RPE atrophy and pigmentation in the mid- and far-peripheral retina. Conclusion Systemic comparative analysis may shed light on the characterization of PPVs in these genes. Our findings provide a brief landscape of PPVs in PRPF genes and the associated phenotypes and emphasize the careful classification of pathogenicity for certain types of variants that warrant further characterization.