Lay Abstract:
Cone-rod dystrophy 1 (cord1) is a form of progressive retinal atrophy (PRA) associated with a prevalent RPGRIP1 genetic variant found in English Springer Spaniels (ESSs). However, significant phenotypic variability is observed among genetically affected ESSs. In our preliminary cross-sectional study (phase 1), we examined over 120 affected dogs from nearly 500 ESSs. Most affected dogs displayed unremarkable routine eye examinations, particularly at younger ages. However, functional retinal testing (electroretinography, ERG) conducted across varying ages revealed extensive variability, suggesting the influence of modifiers on disease expressivity. Our initial genome-wide association study indicated potential modifier loci, though it lacked sufficient power for conclusive results.
We now expand our investigation into a longitudinal study (phase 2) that continues to recruit affected dogs for detailed phenotyping, while extending the assessment long term to capture the variable trajectories of disease progression. Our aim is to identify modifiers that influence the expressivity of cord1 by either protecting against or exacerbating the phenotype. We will explore the correlation between long-term PRA phenotypes and potential modifiers by investigating both known and novel modifiers, as well as acquired factors. New modifiers will be mapped and identified using low-pass and deep whole-genome sequencing. Ultimately, we will establish clinically relevant diagnostics and guidelines that facilitate effective management of cord1 while preserving the ESS gene pool. Establishing the long-term trajectories of cord1 and identifying underlying modifiers will lay the foundation for future research, including the development of therapeutic options such as gene-targeted therapies or nutritional interventions to prevent blindness in affected dogs.