Abstract
Purpose :
To understand the spectrum of mutations and clinical phenotype observed in a set of patients with PRPH2 related retinal degeneration.
Methods :
Clinical and genotype information from 113 different families with PRPH2 mutations were analyzed and compared with information available through literature, ClinVar and LOVD. Analysis of additional patients is in progress.
Results :
The phenotype of patients analyzed with PRPH2 mutations include retinitis pigmentosa (RP), macular dystrophy (MD), adult onset vitelliform macular dystrophy, cone-rod dystrophy (CORD), central areolar choroidal dystrophy (CACD), and pseudo-Stargardt (PS), all autosomal dominant in addition to recessive RP (arRP) and digenic RP with ROM1 mutations.
Currently, a total of 419 variants are reported in ClinVar and are classified as benign, likely benign, pathogenic, likely pathogenic and variants with uncertain significance (VUS). Analysis of 113 pedigrees with disease onset ranging from 11 to 55 years old identified 50 unique and pathogenic PRPH2 variants. Among these are 2 splice-site, 2 deletions, 9 truncating and 37 missense variants. The 828+3A>T variant is observed in patients with a diagnosis of adRP, ad-CORD, CACD, pattern dystrophy and PS phenotypes. The Pro210Arg variant is detected in patients with pattern dystrophy, adRP and Vitelliform macular dystrophy. Another variant Pro210Leu, involving the same codon is associated with only adRP. Two pedigrees were observed with digenic RP with PRPH2-ROM1 variants. ROM1 Leu114fs*131 was identified in a family along with the PRPH2 Leu185Pro heterozygous variant causing CACD. The Leu185Pro alone is reported to be associated with adRP and ad-MD pattern dystrophy. The PRPH2 Arg172Trp heterozygous mutation along with the ROM1 Gly113Glu is observed in a patient with pattern dystrophy while patients with the heterozygous Arg172Trp mutation are reported to develop PS, adRP, Vitelliform macular dystrophy and pattern dystrophy phenotypes. A novel heterozygous 33kb deletion including exon 2-3 of PRPH2 segregated in a pedigree with adRP and pattern dystrophy phenotype.
Conclusions :
Our study confirmed a wide variation in PRPH2 related RD phenotype. Similarly, patients with mutations in both PRPH2 and ROM1 presented diverse phenotypes and the impact of additional mutations in ROM1 on phenotype is unknown. Analysis of additional factors contributing the phenotype variation is warranted.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.