Genotype-phenotype correlations of known and novel variants in the PRPH2 gene.

Abstract

Purpose : Variants in the PRPH2 gene have been previously linked to a plethora of inherited retinal degenerations (IRDs) including retinitis pigmentosa (RP), macular dystrophy (MD), adult vitelliform macular dystrophy, cone-rod dystrophy and many more. This study aimed to correlate known and novel pathogenic variants in PRPH2 with the resulting patient phenotypes.

Methods : Next-generation sequencing of known IRD-associated genes was performed for over 1000 Irish IRD participants with IRD phenotypes. Detailed clinical examinations of all participants carrying a candidate disease-causing variant in PRPH2 were performed to best determine the specific phenotype. The results of these examinations were then compared for differences and consistencies in disease manifestation.

Results : Potentially pathogenic mutations in the PRPH2 gene were established in 18 participants from 15 different families. This accounts for over 2 percent of all resolved genotypes which is consistent with larger studies of a similar nature. 8 out of 18 (44%) of PRPH2 patients presented with a predominantly macular degeneration, while the remaining 10 (56%) patients presented clinically with a RP phenotype. The most prominent variant in this cohort was c.634A>G, p.Ser212Gly. It was present in 8 patients and associated with an autosomal dominant RP (adRP) phenotype. These cases were additional to the previous study of this mutation by the team in a large Irish adRP pedigree. Nine additional PRPH2 variants were observed in the remaining 10 cases, one of which was a novel variant in exon 1 of the gene, c.440dupA, p.Gly148Trpfs*29. These remaining cases presented with a predominately cone-driven degeneration.

Conclusions : Studies such as this are particularly useful for genes associated with multiple phenotypes. The results may help to inform prognoses when dealing with the mutational spectrum of the PRPH2 gene. Although this study was performed on a relatively small subset of IRD participants, we did not observe significant phenotypic variability between patients with the same PRPH2 mutation. Given we are in the era of gene therapy, accurate genetic diagnoses have never been more important to identify needs and enable access to potential future therapeutics.

This is a 2021 ARVO Annual Meeting abstract.