Abstract
Purpose :
The RHO-P23H mutation is a well-known cause of autosomal dominant Retinitis Pigmentosa. Although affected patients share the same primary sequence defect, their phenotype displays a spectrum of disease severity. We hypothesized that the phenotypic variability could be due to an increased mutational load in the known inherited retinal disease (IRD) genes or to a differentially expressed wild-type RHO allele, that alters the ratio of the wild-type and mutant rhodopsin protein. Therefore, we tested for correlation of: 1) sequence variability in known IRD genes; and 2) wild-type RHO allele haplotypes with RHO-P23H phenotype severity.
Methods :
We investigated a cohort of 130 RHO-P23H patients. Variable retinal severity was documented by retrospective analysis of ophthalmological data. We selected electroretinographic (ERG) measurements, in particular the 30Hz flicker ERG amplitude as the most comprehensive single parameter demonstrating phenotypic variability, adjusted for age. Targeted sequencing of all known IRD genes and genotyping of the RHO locus were performed using an in-house sequencing panel and a genotyping array (Illumina GSA), respectively. Deleteriousness of rare IRD variants was assessed using CADD, where for each patient we summed CADD scores for rare (MAF=<0.05) high-impact (loss-of-function) and missense variants. Genotyped variants surrounding the RHO locus (850kb) were phased using Eagle-v2 and samples of European ancestry from the Haplotype Reference Consortium panel.
Results :
No significant correlation (r2<0.01) was observed between retinal disease severity in RHO-P23H patients and the mutational load of rare loss-of-function or missense variants in other known IRD genes. Analysis of the RHO locus confirmed that the RHO-P23H allele is a founder allele in the US population, with only one family showing a different haplotype for the RHO-P23H allele. No particular wild-type allele segregated with mild or severe cases in any of the families.
Conclusions :
Our results do not support two of our original hypotheses: 1) that mutational load in IRD genes can lead to the modulation of RHO-P23H disease severity, and 2) that the wild-type RHO allele can have an effect on disease severity. Differences in disease severity in the RHO-P23H patients may be the result of genetic modifiers elsewhere in the genome.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.