Abstract
Purpose :
Variants in PRPF8, which encodes an integral spliceosome protein, are a well-known cause of autosomal dominant retinitis pigmentosa (RP). The first extraretinal manifestations of PRPF8 variants were recently reported in a cohort with neurodevelopmental delay (NDD) with variable co-occurrence of RP (PMID 3554314). We evaluated PRPF8-associated RP cases at our institution to assess natural history and investigate whether there is a correlation between variant location and phenotype, including the presence of NDD.
Methods :
A retrospective chart review of PRPF8-associated RP cases at Massachusetts Eye and Ear was performed. In silico analyses, gnomAD frequency data, and the literature were used to assess variant pathogenicity. Variants of uncertain significance (VUS) were only included when there was a high probability of being disease-causing. Other genetic causes were ruled out in these cases.
Results :
Twenty-six patients from 22 families were identified carrying 18 unique PRPF8 variants. Eight variants were classified as pathogenic or likely pathogenic with the remainder VUSs. Most were in exons contributing to the C-terminal MPN domain (exon 43, n=19; exon 39 and 42, n=1 each) with the remainder in the RNAase homology (n=4; exons 34 and 37) or the reverse transcriptase domains (exon 22, n=1). Clinical data of varying detail was available for 25 patients. Fourteen had a known family history of RP. Sixteen had symptom onset and/or RP diagnosis by age 12. Symptoms did not begin until the 30’s in 2 patients (exon 34 and 43, n=1 each). Clinical findings included vision-impacting macular atrophy (n=3) and cystoid macular edema (n=6). Two patients had NDD with variants affecting the RNAase homology and reverse transcriptase domains; both had childhood onset of visual symptoms.
Conclusions :
Our cohort demonstrated that PRPF8-associated RP most frequently manifests in childhood. Our identification of two patients with NDD supports recent work describing syndromic PRPF8-associated disease and also adds the reverse transcriptase domain to the RNAase homology domain as a location associated with increased propensity for syndromic presentations. Given the varied age of RP onset, patients with PRPF8 associated NDD who lack RP at initial evaluation should undergo periodic ophthalmic screening.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.