Abstract
Purpose :
PRPH2 (OMIM*179605) encodes a photoreceptor-specific tetraspanin, essential for the formation and maintenance of rod and cone outer segments. The 352 known mutations in PRPH2 are associated with a variety of phenotypes with autosomal dominant, autosomal recessive and digenic inheritance. This study describes the clinical and genetic spectrum across a large multicenter cohort.
Methods :
Patients with pathogenic or likely pathogenic variants in PRPH2 were included from 15 centres across 9 countries. Records were reviewed for age at symptom onset, visual acuity (VA), full-field, pattern, and multifocal electroretinography (ERG), fundus colour photography, fundus autofluorescence (FAF) and optical coherence tomography (OCT). FAF images were graded into six phenotypes: normal, butterfly pattern dystrophy (BPD), vitelliform macular dystrophy (VMD), central areolar choroidal dystrophy (CACD), pseudo-Stargardt pattern dystrophy (PSPD) and retinitis pigmentosa (RP). DNA was tested by next generation sequencing methods or targeted Sanger sequencing. Statistical analyses were performed to determine genotype-phenotype correlations.
Results :
A total of 241 patients were imaged at a median (range) age of 56 (7-89) years. FAF phenotypes included 5% normal, 11% BPD/VMD, 28% CACD, 41% PSPD and 15% RP. Median (range) age at symptom onset was 40 (4-78) years. Twenty patients were asymptomatic. Symptom onset was significantly earlier in RP compared to the PSPD (33.6 vs 44.1 years, p=0.004). Median (IQR) VA (logMAR) was 0.18 (0.00-0.54). ERG showed a significantly reduced amplitude across all components and a peak time delay in the light-adapted (LA) flicker and LA 3.0 b-wave (p<0.001). Of 91 unique variants (n=number of novel variants), there were 46 missense (n=11), 5 in-frame deletions (n=1), 21 frameshift (n=10), 12 nonsense (n=4), 2 exon deletions (n=1), 4 splice-site and 1 start-loss. The CACD FAF phenotype was associated with 13 missense variants at 10 different codon positions. These 13 variants rarely exhibited another FAF phenotype whilst the remaining variants showed normal, BPD/VMD, PSPD and RP phenotypes.
Conclusions :
This work represents the largest cohort of PRPH2 with multimodal imaging. Six distinct FAF phenotypes were described. Given the vast phenotypic spectrum of PRPH2 disease, our findings are useful for defining cohorts for inclusion in future clinical trials.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.