Abstract
Purpose :
Achromatopsia is an autosomal recessive genetic disease, and 95% of achromatopsia patients carry pathogenic mutations in the CNGA3 or CNGB3 genes. Once translated, these proteins function together by forming a cone photoreceptor CNG channel protein complex. This study aimed to elucidate the pathogenicity of CNGA3 variants of unknown significance (VUS) in achromatopsia by creating a three-dimensional (3D) proteotype-based structure-function variant analysis tool.
Methods :
We identified 150 reported CNGA3 missense variants in achromatopsia patients. Of these, 47 were known to be pathogenic, but the pathogenicity of 103 variants remained unknown due to inconclusive genetic information. We used the 47 pathogenic missense variants to create six proteotypic groups with distinctive functional consequences by mapping their spatial proximity in a 3D protein structure of the cone CNGA3/CNGB3 complex. This meta-analysis was further applied to the 103 missense VUS found in achromatopsia patients.
Results :
Structure-function analysis identified 86.4% of VUS that had similar or identical functional consequences to nearby pathogenic variants in 3D, which supports their likelihood of being pathogenic and their potential molecular pathology. The remaining 13.4% of VUS were either located distantly from known pathogenic variants, or significantly different from nearby pathogenic variants in their structural effect.
Conclusions :
3D proteotype-based structure-function analysis of pathogenic CNGA3 missense variants in achromatopsia can be used to help determine the pathogenicity of VUS. This approach provides a complementary tool to traditional clinical genomics.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.