Submission Details

The PRPF4 gene was first reported in relation to autosomal dominant retinitis pigmentosa in 2014 (PMID: 24419317, PMID: 24959063, PMID: 25383878), with cases showing onset of visual symptoms in late adolescence or adulthood. Two subsequent publications have expanded the phenotypic spectrum associated with heterozygous PRPF4 variants to include cases with early childhood onset (PMID: 37264419) or diagnosis of rod-cone dystrophy (PMID: 38184646). The six published cases identified in this curation collectively exhibit a variety of retinal features including reduced visual acuity, nyctalopia, visual field constriction, decreased or absent electroretinogram responses from rods and cones, pigmentary retinopathy, attenuation of retinal blood vessels, optic disc pallor, cataracts, and loss of the outer and inner segments on macular optical coherence tomography. The spectrum of disease also includes a case in which intellectual disability was noted (PMID: 38184646). Some of the families showed evidence of incomplete penetrance among family members harboring the variant. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the shared mode of inheritance (autosomal dominant) and phenotypic overlap among all of these cases informed the decision to combine them into a single gene curation, with the lumped disease entity referred to as PRPF4-related retinopathy.

Six suspected disease-causing variants were scored as part of this curation (four missense and two located in the 5’ untranslated or promoter region), which have been collectively reported in six probands in five publications (PMID: 24419317, PMID: 24959063, PMID: 25383878, PMID: 37264419, PMID: 38184646). At least one family with evidence of co-segregation of the genotype with affected status was identified, but was not sufficiently large to contribute to the scoring of the gene-disease relationship (PMID: 24419317). The mechanism of disease is not yet well-understood, and characterization of individual variants have identified loss-of-function effects such as decreased expression (PMID: 24419317) and loss of protein-protein interactions (PMID: 25383878), as well as neomorphic effects such as disruption of subcellular structures that mediate mRNA splicing and aberrant expression of mRNA splicing factors when exogenously expressed (PMID: 24419317).

This gene-disease association is also supported by experimental evidence indicating that PRPF4 encodes a component of the U4/U6 small nuclear ribonucleoprotein complex within the spliceosome that Is required to remove introns from pre-mRNA molecules to yield mRNA (PMID: 9257651). Although PRPF4 is ubiquitously expressed across human tissues (PMID: 30239781), photoreceptor cells are known to be characterized by a specific splicing program that controls the splicing of mRNAs critical to the development of the primary cilia and outer segments (PMID: 27541351). snRNP complexes includes other components such as PRPF3, PRPF6, PRPF8, PRPF31, and SNRNP200, all of which are encoded by genes linked to monogenic forms of autosomal dominant retinitis pigmentosa. PRPF4 directly interacts with PRPF3 in particular (PMID: 9328476). Fibroblasts from one affected patient show higher and more diffuse staining for a spliceosome marker relative to fibroblasts from an unaffected patient (PMID: 24419317). Zebrafish exogenously expressing a disease-associated variant exhibit defective retinal morphology including loss of the photoreceptor and inner and outer segment layers of the retina (PMID: 24419317). Another variant has shown an inability to rescue zebrafish with Prpf4 knockdown, which causes defects in visual function and loss of photoreceptor outer segments (PMID: 21051334).

In summary, PRPF4 has Moderate evidence of association with PRPF4-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. However, additional genetic evidence and continued characterization of the functional impact of apparent disease-causing variants will be required in order for this gene-disease association to reach a more definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on August 1st, 2024 (SOP Version 10).