Purpose: To characterize photoreceptor layer thinning in clinically unremarkable regions adjacent to the atrophic lesion in early-stage ABCA4 disease eyes. Methods: 27 patients with confined atrophic lesions (≤3.5mm in diameter) were included. Two pathogenic alleles were confirmed by sequencing of the ABCA4 locus. Multimodal imaging included fundus photography, short wavelength and near-infrared-autofluorescence (SW-AF, NIR-AF) imaging. Total receptor+ (TREC+) thickness was segmented in spectral domain-optical coherence tomography (SD-OCT) scans in patient eyes (n=27) along with age-matched healthy control eyes (n=20). Results: Mean (μ) age of the study cohort was 24.1 years and 15/27 (55.6%) patients harbored genotypes consisting of the p.(Gly1961Glu) variant of the ABCA4 gene. Atrophic lesions ranged from 0.61 to 3.13mm in diameter (μ=1.73, σ=0.70). Six patients had mild RPE mottling adjacent to the lesion on NIR-AF. The atrophic lesion corresponded to a disruption of photoreceptor-attributable bands on SD-OCT while all layers were visibly intact outside the lesion. TREC+ thickness in patient eyes were <0.15mm (below 4σ) of healthy control thickness immediately adjacent to the lesion edge and gradually normalized to within ±2σ at ≈1.2mm eccentricity from the fovea. Conclusion: A uniform subclinical perilesional zone (SPZ) of photoreceptor thinning extends around the perimeter of early-stage atrophic lesions in ABCA4 disease. This region spatially maps to known regions of vision loss and more accurately approximates the extent of photoreceptor abnormality compared to disease changes visible on standard fundus imaging. Translational relevance: Semi-automated segmentation of SD-OCT scans identifies a consistent subclinical biomarker that vision loss assessment in patients and the design clinical outcome measures in ABCA4 disease.

SHT has received support from Abeona Therapeutics and is a board member of Emendo Biotherapeutics, Nanoscope Therapeutics and Rejuvitas, Inc.

This work was supported, in part, by the National Eye Institute, NIH grants R01 EY028203, R01 EY028954, R01 EY029315, P30 19007 (Core Grant for Vision Research), the Foundation Fighting Blindness USA, grant no. PPA-1218-0751-COLU, and the unrestricted grant to the Department of Ophthalmology, Columbia University, from Research to Prevent Blindness.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committee/IRB of Columbia University gave ethical approval for this work under protocol #AAAI9906. All study-related procedures adhered to the tenets established by the Declaration of Helsinki.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present work are contained in the manuscript.