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

The fifth adaptor protein complex AP-5, of which AP5B1 encodes a subunit, contributes to endolysosomal trafficking and lysosomal homeostasis; biallelic variants in three of its subunits have been found in families with macular dystrophy.

The AP-5 adaptor complex, involved in endolysosomal trafficking and lysosomal homeostasis, had already been implicated in neurodegenerative syndromes, after which biallelic variants in three of its subunits were identified in families with macular dystrophy, four of them in AP5B1. The authors describe 22 affected individuals from 20 families, all carrying the recurrent missense variant NM_138368.5:c.2354T>C p.(Leu785Pro), either homozygous (16 families) or in trans with another rare AP5B1 missense or loss-of-function variant; five families were of Ashkenazi Jewish and fifteen of European ancestry. The phenotype is a predominantly late-onset macular dystrophy frequently progressing to cone-rod degeneration, with foveal sparing, early peripapillary involvement and a reticular pattern best seen on fundus autofluorescence in the mid- or peripheral retina, the typical presenting symptom being decreased visual acuity. Age at onset ranged from 27 to 74 years, with most individuals symptomatic after the fifth decade, and eight of them had hearing loss.

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The practical value lies in the recurrent nature of the allele: faced with a maculopathy starting after the fifth decade in a patient of European or Ashkenazi Jewish ancestry, homozygosity for p.(Leu785Pro) becomes a first-line hypothesis, including on exomes reported as negative before AP5B1 was annotated as a retinal dystrophy gene. The series is purely observational — no functional data on this missense variant, no population allele frequency estimate allowing penetrance to be approached — and recruitment through retinal centres probably overestimates the proportion of isolated forms. The hearing loss reported in eight patients deserves systematic assessment rather than being treated as incidental.

Analysis by Dr Thibaut Benquey