Spectrum-frequency and genotype-phenotype analysis of rhodopsin variants

Mutations in RHO are the most common cause of autosomal dominant retinitis pigmentosa. However, the pathogenicity of many RHO variants is questionable. This study was designed to investigate the genotype-phenotype correlation for RHO variants. These RHO variants were collected from the in-house exome sequencing data of 7092 probands suffering from different types of eye conditions. The variants were classified using bioinformatics tools, family segregation, and clinical phenotypes. The RHO variants were assessed using multiple online tools and a genotype-phenotype analysis based on the data collected from of ours, gnomAD, and published literature. Totally, 52 heterozygous variants of RHO were detected in the 7092 probands. Of these 52, 17 were potentially pathogenic, were present in 35 families, and comprised 15 missense variants, one inframe deletion and one nonsense variant. All the 15 missense variants were predicted to be damaging by five different online tools. The analysis of the clinical data of the patients from the 35 families revealed certain common features, of an early damage to both the rods and the cones, relatively preserved visual acuity in adulthood, and mid-peripheral tapetoretinal degeneration with pigmentation or RPE atrophy. Our data, the data from gnomAD, and the systematic review of the 246 previously reported variants suggest that approximately two-thirds of the rare missense variants and most of the truncated variants involving upstream of K296 are likely benign. This study provides a brief summary of the characteristics of the pathogenic RHO variants. It emphasizes that the systematic evaluation of these variants at the individual-gene level is crucial in the current era of clinical genetic testing even for a well-known gene such as RHO.