Enhanced genotype-phenotype analysis using multimodal adaptive optics and 3D protein structure in Bietti Crystalline Dystrophy

Purpose: Deep phenotyping of genetic retinal disease using multimodal adaptive optics ophthalmoscopy and protein structure variant analysis.

Observations: In a patient with extensive atrophy of the retinal pigment epithelium and yellow deposits in the retina, genetic testing identified two CYP4V2 variants: c.802-8_810delinsGC and c.1169G > A, p.Arg390His. AI-generated protein structures indicated loss of CYP4V2 function. Reflectance confocal and multiple-scattering Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO) captured crystalline deposits throughout the retina as well as previously unreported cyst-like structures that were mainly independent from the crystalline deposits. Sequential AOSLO imaging was conducted and revealed anatomical and morphological changes in the cysts and surrounding cellular structures.

Conclusions and importance: Cyst-like changes may represent a new BCD degenerative feature. Characterizing retinal genetic disease variants with protein structural modeling and phenotyping with AOSLO represents an advanced approach for clinical diagnosis and may serve as a biomarker of disease progression.