Results of the multicenter study “Registry of patients with inherited retinal dystrophies caused by confirmed biallelic mutations in the RPE65 and RLBP1 genes in Russia (REGINA)”. Report 1. Molecular genetic characteristics of inherited retinal pathologies

Authors:

В. В. Кадышев,

А. А. Степанова,

К. К. Шефер,

И. В. Кондрашина,

Щагина О.А.

Журнал: Вестник офтальмологии. 2026;142(1):70-78.

DOI: 10.17116/oftalma202614201170

Read: 1607 раз

Download PDF (RU)Download PDF (EN)

Abstract

PURPOSE

The primary objective of the study was to investigate and describe the molecular genetic characteristics of patients with inherited retinal dystrophies (IRDs) presenting with phenotypes of Leber congenital amaurosis (LCA) or retinitis pigmentosa (RP), taking into account clinical polymorphism.

MATERIAL AND METHODS

This noninterventional cohort study was conducted in Russia by collecting retrospective data from patients with LCA and RP phenotypes and annual prospective follow-up of patients with IRDs caused by biallelic mutations in the RPE65 or RLBP1 genes, entered into the registry between July 20, 2022 and March 3, 2025. Eligible participants were entered into the IRD database, followed by a two-stage genetic diagnostic algorithm to confirm the presence of biallelic mutations in RPE65 or RLBP1. The data were entered into standardized electronic case report forms, verified, and analyzed using descriptive statistical methods.

RESULTS

The study cohort included 2425 patients with IRDs from 83 regions of the Russian Federation. The mean age was 23.22±16.74 years, with predominance of pediatric patients (51.34%) and males (52.99%).

Genetic testing was performed in two stages. At the first stage, mutations in RPE65 and/or RLBP1 were identified in 84 (3.52%) of 2388 examined patients. The second stage involving direct Sanger sequencing was conducted in 48 (2.01%) patients, it confirmed biallelic mutations in RPE65 in 1.68% and in RLBP1 in 0.04% of cases. In one case, mutations in both genes were verified. Among RPE65 variants, 61 mutations were identified, including frequent pathogenic variants (c.304G>T, c.272G>A, c.370C>T); seven variants were detected in the RLBP1 gene.

The frequency of biallelic RPE65 mutations in the subgroup with LCA/RP phenotype was 1.68%, and 1.65% in the overall IRD cohort, which is consistent with published data from European populations.

CONCLUSION

The study “Registry of patients with inherited retinal dystrophies caused by confirmed biallelic mutations in the RPE65 and RLBP1 genes in Russia” allowed characterization of the key molecular genetic features of a representative sample of patients with IRDs.

Keywords

inherited retinal dystrophy (IRD)
noninterventional study
RPE65
RLBP1
genotype
retinitis pigmentosa
Leber congenital amaurosis
eye
gene
prevalence
genetic diagnostics
genetic heterogeneity
clinical polymorphism

Дата поступления: 17.02.2026

Дата принятия в печать: 24.02.2026

Дата публикации: 18.03.2026

References

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010;29(5):335-375. https://doi.org/10.1016/j.preteyeres.2010.03.004
Duncan JL, Pierce EA, Laster AM, et al. Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps. Transl Vis Sci Technol. 2018;7(4):6. Published 2018 Jul 18. https://doi.org/10.1167/tvst.7.4.6
Kady’shev VV. Nasledstvenny’e zabolevaniya glaz: e’pidemiologiya, geneticheskaya geterogennost’, klinicheskij polimorfizm: diss. dokt. med. nauk. 2023. — 391 s. — EDN DTGJLV. (In Russ.). https://elibrary.ru/item.asp?id=59961682
Aver’yanova SV, Yur’eva TN, Kady’shev VV. Genetic heterogeneity and phenotypic diversity of hereditary retinal pigmented dystrophy. Fyodorov Journal of Ophthalmic Surgery. 2025;1(143): 129-136. (In Russ.). https://doi.org/10.25276/0235-4160-2025-1-129-136
Murro V, Banfi S, Testa F, Iarossi G, Falsini B, Sodi A, Signorini S, Iolascon A, Russo R, Mucciolo DP, Caputo R, Bacci GM, Bargiacchi S, Turco S, Fortini S, Simonelli F. A multidisciplinary approach to inherited retinal dystrophies from diagnosis to initial care: a narrative review with inputs from clinical practice. Orphanet J Rare Dis. 2023 Jul 31;18(1):223. https://doi.org/10.1186/s13023-023-02798-z
O’Neal TB, Tripathy K, Luther EE. Retinitis Pigmentosa. [Updated 2024 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. https://www.ncbi.nlm.nih.gov/books/NBK519518
Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018;66:157-186. https://doi.org/10.1016/j.preteyeres.2018.03.005
Cross N, van Steen C, Zegaoui Y, Satherley A, Angelillo L. Retinitis Pigmentosa: Burden of Disease and Current Unmet Needs. Clin Ophthalmol. 2022;16:1993-2010. https://doi.org/10.2147/OPTH.S365486
Koenekoop RK. An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol. 2004;49(4):379-398. https://doi.org/10.1016/j.survophthal.2004.04.003
Stone EM. Leber congenital amaurosis — a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 2007;144(6):791-811. https://doi.org/10.1016/j.ajo.2007.08.022
Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX. RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci U S A. 2005;102(35): 12413-12418. https://doi.org/10.1073/pnas.0503460102
Morimura H, Fishman GA, Grover SA. et al. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A. 1998;95(6):3088-3093.
Chung DC, Bertelsen M, Lorenz B. et al. The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene. Am J Ophthalmol. 2019;199:58-70. https://doi.org/10.1016/j.ajo.2018.09.024
Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860. https://doi.org/10.1016/S0140-6736(17)31868-8
Bennett J, Wellman J, Marshall KA, et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet. 2016;388(10045):661-672. https://doi.org/10.1016/S0140-6736(16)30371-3
Neroev VV, Katargina LA, Kady’shev VV, Zol’nikova IV, Kucev SI. Prospects for the diagnosis and gene therapy of inherited retinal dystrophies caused by biallelic mutations in the RPE65 gene. Russian ophthalmological journal= Rossijskij oftal’mologicheskij zhurnal. 2021;14(3):78-82. (In Russ.). https://doi.org/10.21516/2072-0076-2021-14-3-78-82
Sajdasheva E’I, Kady’shev VV, Brzheskij VV, Malinovskaya NA, Shefer KK. A decision making algorithm for inherited retinal dystrophies, caused by biallelic mutations in the RPE65 gene, in the clinical practice of an ophthalmologist. Russian ophthalmological journal = Rossijskij oftal’mologicheskij zhurnal. 2022;15(1):113-116. (In Russ.). https://doi.org/10.21516/2072-0076-2022-15-1-113-116
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 613794: 04/27/2023. Accessed: 12.09.2025. https://omim.org
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 204100: 04/27/2023. Accessed: 12.09.2025. https://omim.org
Bocquet B, El Alami Trebki H, Roux AF, et al. Retinitis Punctata Albescens and RLBP1-Allied Phenotypes: Phenotype-Genotype Correlation and Natural History in the Aim of Gene Therapy. Ophthalmol Sci. 2021;1(3):100052. https://doi.org/10.1016/j.xops.2021.100052
Morimura H, Berson EL, Dryja TP. Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest Ophthalmol Vis Sci. 1999;40(5):1000-1004.
Kvanta A, Rangaswamy N, Holopigian K, et al. Interim safety and efficacy of gene therapy for RLBP1-associated retinal dystrophy: a phase 1/2 trial. Nat Commun. 2024;15(1):7438. Published 2024 Sep 10. https://doi.org/10.1038/s41467-024-51575-4
Pérez-Palma E, Gramm M, Nürnberg P, May P, Lal D. Simple ClinVar: an interactive web server to explore and retrieve gene and disease variants aggregated in ClinVar database. Nucleic Acids Res. 2019;47(W1):W99-W105. https://doi.org/10.1093/nar/gkz411
Landrum MJ, Lee JM, Benson M, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1): D862-D868. https://doi.org/10.1093/nar/gkv1222
Rehm HL, Berg JS, Brooks LD, et al. ClinGen-the Clinical Genome Resource. N Engl J Med. 2015;372(23):2235-2242. https://doi.org/10.1056/NEJMsr1406261
Sallum JMF, Kaur VP, Shaikh J, et al. Epidemiology of Mutations in the 65-kDa Retinal Pigment Epithelium (RPE65) Gene-Mediated Inherited Retinal Dystrophies: A Systematic Literature Review. Adv Ther. 2022;39(3):1179-1198. https://doi.org/10.1007/s12325-021-02036-7
Holtan JP, Selmer KK, Heimdal KR, Bragadóttir R. Inherited retinal disease in Norway — a characterization of current clinical and genetic knowledge. Acta Ophthalmol. 2020;98(3):286-295. https://doi.org/10.1111/aos.14218
Eisenberger T, Neuhaus C, Khan AO, et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013;8(11):e78496. https://doi.org/10.1371/journal.pone.0078496
Booij JC, Florijn RJ, ten Brink JB, et al. Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. J Med Genet. 2005;42(11):e67. https://doi.org/10.1136/jmg.2005.035121
Issa M, Sukkarieh G, Bruneau S, Tadayoni R. A novel rlbp1 gene mutation associated with retinal flecks. Retin Cases Brief Rep. 2025;19(3):376-378. https://doi.org/10.1097/ICB.0000000000001574