The landscape of variants in pre-mRNA-processing factor genes in an Irish cohort.

PURPOSE: Variants in pre-messenger RNA (mRNA) processing genes account for ∼15% to 20% of autosomal dominant retinitis pigmentosa, causing severe vision loss. We provide an in-depth characterization of pre-mRNA-processing variants in the population, with a focus on genotype-phenotype correlations.

METHODS

Participants underwent next-generation sequencing, variant filtering and interpretation. Impact(s) on protein structure/function were predicted through AlphaFold, ColabFold, among others. Clinical information was collated and segregation analysis undertaken. Variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.

RESULTS

A total of 635 patients with retinitis pigmentosa (RP) were screened. Notably, 36 different variants were identified in PRPF31, PRPF8, SNRNP200, PRPF3, RP9, and PRPF 6; 19 were classified as likely pathogenic/pathogenic. Thirteen of 36 variants were absent from PubMed, gnomAD, LOVD, and ClinVar, with an additional 10 not previously associated with retinal degeneration. Genotype-phenotypes correlations were illuminated; variants in PRPF genes caused more severe retinal degeneration than SNRNP200 variants.

CONCLUSION

We provide a detailed overview of the genetic landscape of variants in pre-mRNA-processing factor genes in Ireland, accounting for 14% of genetically solved autosomal dominant retinitis pigmentosa cases. Results highlight significant genetic diversity between populations, mutational diversity inherent in inherited retinal degenerations and the role of variants in mRNA-processing genes as causative of devastating ocular disorders.