The AP5B1 p.Leu785Pro variant is a frequent cause of late-onset macular dystrophy with variable extraocular manifestations.

Inherited retinal diseases (IRDs) represent a large group of genetically heterogeneous disorders that often cause progressive visual loss. The fifth adaptor protein (AP-5) complex, which contributes to endolysosomal trafficking and lysosomal homeostasis, has previously been implicated in neurodegenerative syndromes, and more recently, bi-allelic variants in three of its subunits were found in families with macular dystrophy, including four with variants in AP5B1. Here, we describe 22 affected individuals from 20 families with AP5B1-associated IRD, all carrying the recurrent missense variant c.2354T>C (GenBank: NM_138368.5) (p.Leu785Pro), either in the homozygous state (16 families) or in trans with another rare heterozygous AP5B1 missense or loss-of-function variant. Five families were of Ashkenazi Jewish ancestry and 15 families of European ancestry. Clinically, affected individuals presented with a predominantly late-onset macular dystrophy that frequently progressed to cone-rod degeneration. Characteristic retinal findings included foveal sparing, early peripapillary involvement, and a reticular pattern best observed by fundus autofluorescence imaging in the mid- or peripheral retina. The typical presenting symptom was decreased visual acuity. Age at onset ranged from 27 to 74 years, with most individuals becoming symptomatic after the fifth decade of life. Some individuals also presented with extraocular manifestations, most notably hearing loss, which was reported in 8 affected individuals. These findings further support AP5B1 as a cause of macular dystrophy, identify p.Leu785Pro as a relatively frequent pathogenic allele in individuals of European and Ashkenazi Jewish ancestry, and expand the associated phenotypic spectrum to include both isolated macular dystrophy and possible syndromic presentations.