Inherited Retinal Disease or Age-Related Macular Degeneration: Predictive Value of Genetic Testing in Macular Disease...

Both age-related macular degeneration (AMD) and inherited retinal disease (IRD) can present with outer retinal atrophy at the macula. Distinguishing between IRD and geographic atrophy (GA) secondary to AMD is important for appropriate management, particularly as disease-specific treatments become available. This study investigates the utility of genetic testing for suspected IRDs in individuals with atypical macular atrophy.

Twenty-four participants aged over 50, presenting with macular atrophy atypical for AMD, underwent clinical assessments, multimodal retinal imaging and exome-based sequencing covering known IRD genes. Three retinal ophthalmologists reviewed genetic and clinical data to reach a consensus for the underlying cause of macular atrophy and identified a set of features that challenge an AMD diagnosis and suggest a higher likelihood of an IRD.

The panel judged 58% of atypical atrophy cases as likely being an IRD. Of these suspected cases, 57% (33% of the entire cohort) received IRD genetic confirmation (PRPH2, ABCA4 or MT-TL1 [m.3243A>G]-related IRD). The remaining cases were classified as GA (29%) or did not reach consensus on the likely diagnosis (13%). Clinical features aiding in the differentiation of IRD from GA included symptom onset before age 50, family history, distinctive autofluorescence patterns (speckled, reticular or widespread), extensive atrophy and absence of subretinal drusen.

IRD genetic testing is valuable if a positive identification is achieved, but negative results neither rule out IRD nor confirm AMD. Limitations in our ability to robustly differentiate IRD-related atrophy from GA, especially in advanced lesions, need further research to improve diagnostic accuracy.