PRPH2 Gene Mutations and Associated Phenotypes in IRD patients with diverse genetic background.

Abstract

Purpose : The aim of this study was to investigate the spectrum of pathogenic variants in the PRPH2 gene and their correlation with different phenotypes in patients of diverse genetic backgrounds.

Methods : Patients from diverse ethnic backgrounds and geographical regions were enrolled. Comprehensive demographic, familial, and medical histories were collected. Ophthalmic evaluations including fundus examination, fluorescent angiography, OCT, and ERG were performed in select cases. Genetic analysis included whole genome or whole exome sequencing, targeted sequencing of relevant genes, to sequencing of the PRPH2 gene alone, and subsequent phenotype-genotype associations.

Results : A total of 784 patients with pathogenic variants in PRPH2 were included, (394 females and 388 males from 597 families). Majority of patients were of European descent (55%), while the rest included individuals from Middle Eastern, African American, Asian, Native American, Pacific Islander, Hispanic, and mixed racial backgrounds. Clinical diagnoses revealed 12 major phenotypes, with macular dystrophy (38%), RP (24%), and pattern dystrophy (13%) being the most common and 4% with no clinical symptoms. Ages of those with no retinal phenotype ranged from 11-47. Three families with homozygous pathogenic variants, c.441del and c.655C>G, were diagnosed with LCA. Genetic analysis unveiled 163 unique mutations, categorized as missense, nonsense, frameshift, splice site, duplication, and large deletions. Seventy-four patients with data on additional mutations in genes linked to dominant and recessive IRDs revealed that 60 of these have only one, 11 have 2, two have 3, and one has 4 potentially pathogenic variants in additional genes. Further, among 61 patients with data on c.910G>C/A/T, c.929C>T/A/G and c.1013T>C/G>A/G>T PRPH2 SNP haplotype 44 had homozygous, 5 had heterozygous and 12 had mixed haplotypes. The common PRPH2 variations varied across different ethnicities and a broad intrafamilial and interfamilial phenotypic variation was observed.

Conclusions : This analysis underscores the diverse phenotypic manifestations associated with PRPH2 gene mutations in our cohort. Analysis to determine the impact of supplementary potentially pathogenic variants in other IRD genes and/or the PRPH2 common SNP haplotypes on phenotype is in progress.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.