Prevalence estimates and genetic diversity for autosomal dominant retinitis pigmentosa due to RHO, c.68C>A (p.P23H) variant

Abstract

ObjectiveTo provide the most up-to-date clinical prevalence estimate for autosomal dominant retinitis pigmentosa (adRP) patients due to RHO c.68C>A, (p.P23H) in the United States, supported by two independent approaches; literature based meta-analysis of reported patients and population genetics modeling. DesignSystematic review and meta-analysis plus population genetics modeling. MethodsSystematic review of the literature describing RP patients attributed to RHO variants was conducted to support a meta-analysis used to estimate the clinical prevalence of the RHO P23H patients diagnosed in the US. In parallel, large-scale genetic diversity studies describing the US population and non-European cohorts of the Americas (PAGE II), were evaluated to ascertain the allele frequencies of variant RHO c.68C>A, (p.P23H). The genetic prevalence for variant RHO c.68C>A, (p.P23H) was calculated using Hardy-Weinberg equilibrium. Further demographic data, including age and average age of onset for visual impairment were incorporated into a basic distribution model to estimate clinical prevalence of genetically predisposed persons. ResultsThe estimated clinical prevalence of adRP due to RHO P23H based on literature review was approximately 2000-3000 patients. In comparison the genetic prevalence of persons with RHO c.68C>A, (p.P23H) in the United States was an estimated 6176 (90% CI: 3333-11398) and only half of them are expected to cluster with European genetic ancestry. This variant was found enriched in subgroups of African American or other non-European biogeographic ancestries. Of the estimated 6200 persons carrying this variant in the US, ∼3500 (estimate range: 1900-6500) are expected to show clinical signs of visual impairment as modeled by average age of onset previously reported for patients with this variant. ConclusionsWe utilized two independent approaches to estimate the total number of adRP patients due to RHO c.68C>A, (p.P23H) in the United States; systematic literature review based meta-analysis and population genetics modeling. Both approaches yielded similar, overlapping estimates of adRP patients due to RHO P23H. However, comparison of these estimates provides some indication for a diagnosis gap. Unexpectedly, this variant is present at relatively higher frequency in some predominantly non-European genetic ancestries in the US. While this genetic analysis supports our estimates of clinical prevalence of adRP due to RHO P23H in the United States, it also has implications for diagnosing potential adRP patients due to this variant, raising questions of genotype-phenotype correlation and access to genetic testing.