@article{10.1172/jci.insight.155373, author = {Maximilian Pfau AND Catherine A. Cukras AND Laryssa A. Huryn AND Wadih M. Zein AND Ehsan Ullah AND Marisa P. Boyle AND Amy Turriff AND Michelle A. Chen AND Aarti S. Hinduja AND Hermann E.A. Siebel AND Robert B. Hufnagel AND Brett G. Jeffrey AND Brian P. Brooks}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Photoreceptor degeneration in ABCA4-associated retinopathy and its genetic correlates}, year = {2022}, month = {1}, volume = {7}, url = {https://insight.jci.org/articles/view/155373}, abstract = {BACKGROUND Outcome measures sensitive to disease progression are needed for ATP-binding cassette, sub-family A, member 4–associated (ABCA4-associated) retinopathy. We aimed to quantify ellipsoid zone (EZ) loss and photoreceptor degeneration beyond EZ-loss in ABCA4-associated retinopathy and investigate associations between photoreceptor degeneration, genotype, and age.METHODS We analyzed 132 eyes from 66 patients (of 67 enrolled) with molecularly confirmed ABCA4-associated retinopathy from a prospective natural history study with a median [IQR] follow-up of 4.2 years [3.1, 5.1]. Longitudinal spectral-domain optical coherence tomography volume scans (37 B-scans, 30° × 15°) were segmented using a deep learning (DL) approach. For genotype-phenotype analysis, a model of ABCA4 variants was applied with the age of criterion EZ-loss (6.25 mm2) as the dependent variable.RESULTS Patients exhibited an average (square-root-transformed) EZ-loss progression rate of [95% CI] 0.09 mm/y [0.06, 0.11]. Outer nuclear layer (ONL) thinning extended beyond the area of EZ-loss. The average distance from the EZ-loss boundary to normalization of ONL thickness (to ±2 z score units) was 3.20° [2.53, 3.87]. Inner segment (IS) and outer segment (OS) thinning was less pronounced, with an average distance from the EZ-loss boundary to layer thickness normalization of 1.20° [0.91, 1.48] for the IS and 0.60° [0.49, 0.72] for the OS. An additive model of allele severity explained 52.7% of variability in the age of criterion EZ-loss.CONCLUSION Patients with ABCA4-associated retinopathy exhibited significant alterations of photoreceptors outside of EZ-loss. DL-based analysis of photoreceptor laminae may help monitor disease progression and estimate the severity of ABCA4 variants.TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01736293.FUNDING National Eye Institute Intramural Research Program and German Research Foundation grant PF950/1-1.}, number = {2}, doi = {10.1172/jci.insight.155373}, url = {https://doi.org/10.1172/jci.insight.155373}, }