Cross-Sectional Analysis of Outer Retinal Tubulation in Inherited Retinal Diseases: A Multicenter Study

Abstract

PurposeThis study aims to explore genetic variants that potentially lead to outer retinal tubulation (ORT), estimate the prevalence of ORT in these candidate genes, and investigate the clinical etiology of ORT in patients with inherited retinal diseases (IRDs), with respect to each gene. DesignRetrospective cohort study. MethodsA retrospective cross-sectional review was conducted on 565 patients with molecular diagnoses of IRD, confirming the presence of ORT as noted in each patient's respective spectral-domain optical coherence tomography (SD-OCT) imaging. Using SD-OCT imaging, the presence of ORT was analyzed in relation to specific genetic variants and phenotypic characteristics. Outcomes included the observed ORT frequencies across two gene-specific cohorts: non- retinal pigment epithelium (RPE)-specific genes, and RPE-specific genes; and to investigate the analogous characteristics caused by variants in these genes. ResultsAmong the 565 patients included in this study, 104 exhibited ORT on SD-OCT. We observed ORT frequencies among the following genes from our patient cohort: 100% (23/23) forCHM, 100%(2/2) forPNPLA6, 100% (4/4) forRCBTB1, 100% formtDNA[100% (4/4) forMT-TL1and 100% (1/1) formtDNAdeletion], 100% (1/1) forOAT, 95.2% (20/21) forCYP4V2, 72.7% (8/11) forCHMfemale carriers, 66.7% (2/3) forC1QTNF5, 57.1% (8/14) forPROM1, 53.8% (7/13) forPRPH2, 42.9% (3/7) forCERKL, 28.6% (2/7) forCDHR1, 20% (1/5) forRPE65, 4% (18/445) forABCA4.In contrast, ORT was not observed in any patients with photoreceptor-specific gene variants, such asRHO(n=13),USH2A(n=118),EYS(n=70),PDE6B(n=10),PDE6A(n=4),and others. ConclusionThese results illustrate a compelling association between the presence of ORT and IRDs caused by variants in RPE-specific genes, as well as non-RPE-specific genes. In contrast, IRDs caused by photoreceptor-specific genes are typically not associated with ORT occurrence. Further analysis revealed that ORT tends to manifest in IRDs with milder intraretinal pigment migration (IPM), a finding that is typically associated with RPE-specific genes. These findings regarding ORT, genetic factors, atrophic patterns in the fundus, and IPM provide valuable insight into the complex etiology of IRDs. Future prospective studies are needed to further explore the association and underlying mechanisms of ORT in these contexts.