Submission Details

The PRPF8 gene (previously called PRPC8) was first reported in relation to autosomal dominant retinitis pigmentosa in 2001 (McKie et al., PMID: 11468273). PRPF8-related retinitis pigmentosa is now estimated to cause 2-3% of cases of autosomal dominant retinitis pigmentosa, characterized by classic presentation of night blindness and constriction of visual fields in multiple large families. We found PRPF8-related disease is inherited in an autosomal dominant pattern, with monoallelic disease-associated PRPF8 variants causing classic retinitis pigmentosa; age of onset and severity of disease appears to be variable, with some published families displaying reduced penetrance (PMID: 22039234). Despite variability in severity, cases share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, PRPF8-related retinopathy. Other non-retinal diseases related to PRPF8 (glaucoma, myeloid leukemia) have also been described but have been excluded from this curation.

9 suspected disease-causing variants (2 nonsense and 7 missense or other variants) that have been reported in 9 probands in 7 publications (PMIDs: 17061239, 11468723, 11910553, 18695108, 29087248, 28076437, 22039234) were scored in this curation. Most of the reported variants are missense substitutions near the terminal exon of the coding sequence; several nonsense variants in the same region have also been associated with PRPF8-related disease in multiple publications (PMIDs: 29087248, 28076437). Only a few disease-causing variants have been described outside of this C-terminal region (PMIDs: 28761320, 22039234). Some variants (p.H2309P and p.H2309R) are reported to associate with a worse visual prognosis than others (such as p.R2310K, PMID: 20232351). More evidence is available in the literature but has not been included in this curation as the maximum for genetic evidence has already been reached.

The mechanism of pathogenicity appears to be loss of spliceosome function; PRPF8 is the largest protein found in the spliceosome, and appears to inhibit the helicase activity of Brr2/SNRPN200 (PMID: 23727230). C-terminal mutations located in the Jab1 domain of PRPF8 are thought to result in reduction of PRPF8 interaction with a Brr2 (PMID: 19098916). Nonsense variants have also been associated with disease; it is predicted that C-terminal stop mutations may escape nonsense mediated decay, resulting in a truncated protein product that also reduces Brr2 interaction and increases helicase activity (PMID: 23704370). While genotype-phenotype correlations have not been well established, all reported retinopathy-causing variants except one (PMID: 33994920) are located in the C-terminal portion of the gene.

The PRPF8 gene is highly conserved in mammalian and lower vertebrate species, as it encodes a component of splicing machinery. The gene-disease association is supported by multiple cell culture models from model organisms and patient-derived tissue, demonstrating the role of PRPF8 in splicing. Multiple vertebrate and invertebrate models also support the gene-disease association. A drosophila mutant, in which adult eye morphology is dramatically disrupted, is consistent with a role for PRPF8 in photoreceptors (PMID: 32424050). A zebrafish mutant also demonstrates gross neurological differences and splicing disruption, supporting the role of the PRPF8 in splicing and snRNP assembly (PMID: 23714367). Retinal structures in mouse models demonstrate late-onset degenerative changes (PMID: 20811066).

In summary, PRPF8 is definitively associated with PRPF8-related retinopathy; to date, the only associated phenotype is retinitis pigmentosa. The association with retinopathy has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on April 6th, 2023 (SOP Version 9).