Fig. 5: Fundus photography and autofluorescence of representative cases and proposed diagnostic flow chart for IRDs.

a Different genotypes of RP cannot be differentiated by fundus examination, which shared common features, including pale disc, vessel attenuation, and pigmentary change, only with different disease severity. Moreover, the fundus appearance of CD/CRD and STGD is also undistinguishable, both with characteristic central maculopathy. However, the fundus appearance of BCD was characterized by crystalline deposition and could be differentiated easily from other IRDs. b we proposed a diagnostic flow chart to facilitate the early diagnosis of IRDs by incorporating clinical information, metabolomics analysis, and genetic diagnosis. IRDs belonging to rod-predominant disease, cone-predominant disease, and crystalline deposition were first determined by fundus examination. By incorporating targeted metabolomics analysis and a machine learning model, we could further differentiate EYS and USH2A genotypes in rod-predominant disease and STGD and CD/CRD in cone-predominant disease. Finally, we could reach a targeted, small panel NGS for the patient’s and family members' genetic diagnosis. IRD, inherited retinal degeneration; BCD, Bietti’s crystalline dystrophy, CD/CRD, cone dystrophy/cone-rod dystrophy, RP, retinitis; STGD, Stargardt disease, NGS, next-generation sequencing.