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

Pei-Kang Liu; Winston Lee; Pei-Yin Su; Angela H Kim; Eugene Yu-Chuan Kang; Sarah R Levi; Laura A Jenny; Pei-Hsuan Lin; Yi-Chun Chi; Pei-Liang Wu; Ethan Hung-Hsi Wang; Yo-Chen Chang; Laura Liu; Kuan-Jen Chen; Yih-Shiou Hwang; Wei-Chi Wu; Chi-Chun Lai; Stephen H Tsang; Rando Allikmets; Nan-Kai Wang

doi:10.1016/j.ajo.2024.07.032

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

Am J Ophthalmol. 2024 Aug 8:269:116-135. doi: 10.1016/j.ajo.2024.07.032. Online ahead of print.

Authors

Pei-Kang Liu¹, Winston Lee², Pei-Yin Su², Angela H Kim², Eugene Yu-Chuan Kang³, Sarah R Levi², Laura A Jenny², Pei-Hsuan Lin⁴, Yi-Chun Chi⁵, Pei-Liang Wu⁶, Ethan Hung-Hsi Wang⁷, Yo-Chen Chang⁵, Laura Liu⁸, Kuan-Jen Chen⁹, Yih-Shiou Hwang⁹, Wei-Chi Wu⁹, Chi-Chun Lai¹⁰, Stephen H Tsang¹¹, Rando Allikmets¹¹, Nan-Kai Wang¹²

Affiliations

¹ From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; Department of Ophthalmology (P-K.L., Yi-C.C., Yo-C.C.), Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine (P-K.L., Yi-C.C., Yo-C.C.), College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
² From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA.
³ From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; Department of Ophthalmology (E.Y-C.K., L.L., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; College of Medicine (E.Y-C.K., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences (E.Y-C.K.), College of Medicine, Chang Gung University, Taoyuan, Taiwan; College of Arts and Sciences (E.H-H.W.), University of Miami, Coral Gables, Florida, USA.
⁴ From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; Department of Ophthalmology (P-H.L.), National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
⁵ Department of Ophthalmology (P-K.L., Yi-C.C., Yo-C.C.), Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine (P-K.L., Yi-C.C., Yo-C.C.), College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁶ From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; College of Medicine (P-L.W.), National Taiwan University, Taipei, Taiwan.
⁷ From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; College of Arts and Sciences (E.H-H.W.), University of Miami, Coral Gables, Florida, USA.
⁸ Department of Ophthalmology (E.Y-C.K., L.L., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; School of Traditional Chinese Medicine (L.L.), Chang Gung University, Taoyuan, Taiwan.
⁹ Department of Ophthalmology (E.Y-C.K., L.L., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; College of Medicine (E.Y-C.K., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung University, Taoyuan, Taiwan.
¹⁰ Department of Ophthalmology (E.Y-C.K., L.L., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; College of Medicine (E.Y-C.K., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung University, Taoyuan, Taiwan; Department of Ophthalmology (C-C.L.), Chang Gung Memorial Hospital, Keelung, Taiwan.
¹¹ From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; Department of Pathology and Cell Biology (S.H.T., R.A.), Columbia University Medical Center, New York, New York, USA; Vagelos College of Physicians and Surgeons (S.H.T., R.A., N-K.W.), Columbia University, New York, New York, USA.
¹² From the Department of Ophthalmology (P-K.L., W.L., P-Y.S., A-H.K., E.Y-C.K., S.R.L., L.A.J., P-H.L., P-L.W., E.H-H.W., S.H.T., R.A., N-K.W.), Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA; Department of Ophthalmology (E.Y-C.K., L.L., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; College of Medicine (E.Y-C.K., K-J.C., Y-S.H., W-C.W., C-C.L., N-K.W.), Chang Gung University, Taoyuan, Taiwan; Vagelos College of Physicians and Surgeons (S.H.T., R.A., N-K.W.), Columbia University, New York, New York, USA. Electronic address: wang.nankai@gmail.com.

PMID: 39127396
DOI: 10.1016/j.ajo.2024.07.032

Abstract

Purpose: This 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.

Design: Retrospective cohort study.

Methods: A 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 2 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.

Results: Among 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) for CHM, 100% (2/2) for PNPLA6, 100% (4/4) for RCBTB1, 100% for mtDNA [100% (4/4) for MT-TL1 and 100% (1/1) for mtDNA deletion], 100% (1/1) for OAT, 95.2% (20/21) for CYP4V2, 72.7% (8/11) for CHM female carriers, 66.7% (2/3) for C1QTNF5, 57.1% (8/14) for PROM1, 53.8% (7/13) for PRPH2, 42.9% (3/7) for CERKL, 28.6% (2/7) for CDHR1, 20% (1/5) for RPE65, 4% (18/445) for ABCA4. In contrast, ORT was not observed in any patients with photoreceptor-specific gene variants, such as RHO (n = 13), USH2A (n = 118), EYS (n = 70), PDE6B (n = 10), PDE6A (n = 4), and others.

Conclusions: These 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.

Abstract

Grants and funding