Type of mutations
Coding descriptions below use NM_006445.4. Protein-only entries follow the original reports.
Heterozygous missense and predicted loss-of-function variants have been reported in the neurodevelopmental presentation. Reported missense examples include p.(Asp215Gly), p.(Glu295Lys), p.(Asp989Gly), p.(Ala1006Val), p.(Thr1297Lys), p.(Ser1851Phe), p.(Arg1865Thr) and p.(Ser2233Thr), together with the frameshift p.(Tyr2127LeufsTer10) in the original cohort. The evidence supporting individual variants varies, and predicted loss of function requires transcript-specific assessment rather than being treated as a phenotype prediction (O'Grady et al., 2022).
RP13-associated variants show strong C-terminal clustering: c.6926A>C, p.(His2309Pro); c.6929G>A, p.(Arg2310Lys); and c.6942C>G, p.(Phe2314Leu). The terminal nonsense variant c.7002T>G, p.(Tyr2334Ter), has also been reported with retinal disease and is not expected to trigger nonsense-mediated decay (McKie et al., 2001; Towns et al., 2010).
The stop-gain variant c.5548C>T, p.(Arg1850Ter), in the RNase H homology domain was reported in an adolescent with hypophosphataemia, growth hormone deficiency and a partially empty sella (Koljonen et al., 2025).
The missense variants p.(Pro13Leu), p.(Met25Thr) and p.(Val965Gly) have been reported in association with primary open-angle glaucoma. These should be treated as reported associations, and they do not establish the variants as causes of neurodevelopmental disorder (Micheal et al., 2018).
The homozygous variant c.257G>T, p.(Arg86Met), identified in three affected relatives, remains a candidate recessive association. Segregation and computational protein modelling do not substitute for functional validation or independent replication (Mirinezhad et al., 2025).
Genetic testing
Testing may use a phenotype-appropriate panel, exome or genome sequencing, with parental testing where possible. Record the transcript and its version, the HGVS description, zygosity and inheritance.
Interpret variants using clinical laboratory standards and disease-specific evidence. Gene membership alone is insufficient to establish causality, and a variant of uncertain significance should not be presented as a confirmed diagnosis or used alone for predictive reproductive decisions.
Distinguish established RP13, reported glaucoma associations and coincident eye findings when counselling. Ophthalmic risk should not be inferred from the gene name alone.
Suspected pathophysiologic mechanism
PRPF8 encodes a central scaffolding protein of the U4/U6.U5 tri-snRNP, which is required for processing precursor messenger RNA. Disrupted splicing provides the biological link to disease.
Functional work in patient-derived retinal cells implicates dysregulation of the Brr2 helicase by PRPF8, with altered spliceosome kinetics and 5'-splice-site selection, and predominantly retinal and ciliary transcript effects. This retinal mechanism should not automatically be applied to every neurodevelopmental variant (Atkinson et al., 2024).
PRPF8