Inherited Retinal Diseases Due to RPE65 Variants: From Genetic Diagnostic Management to Therapy
Open accessAbstract
Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6–6% of RP and 3–16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants (RPE65-IRDs). Therefore, the accurate molecular diagnosis of RPE65-IRDs is crucial to identify ‘actionable’ genotypes—i.e., genotypes that may benefit from the treatment—and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients’ access to available therapeutic options.
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LCA and EOSRD are characterized by severe visual loss from birth or early infancy, wandering nystagmus, amaurotic pupils, and markedly reduced or non-recordable full-field electroretinograms.
“LCA and EOSRD are characterized by severe visual loss from birth or early infancy, wandering nystagmus, amaurotic pupils, and markedly reduced or non-recordable full-field electroretinograms [112,113].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [112]
Pathogenic variants in RPE65 account for approximately 3% to 16% of LCA and EOSRD patients.
“Pathogenic variants in RPE65 gene account for approximately 3% to 16% of LCA and EOSRD patients [112].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [112]
Most individuals with RPE65-related LCA/EOSRD are legally blind by the age of 40.
“Most individuals are legally blind by the age of 40 [112].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [112]
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- Authors
- Aoun, M., Passerini, I., Chiurazzi, P., Karali, M., De Rienzo, I., Sartor, G., Murro, V., Filimonova, N., Seri, M., & Banfi, S.
- Affiliations
- Novartis (Italy) (IT)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- Università Cattolica del Sacro Cuore (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Department of Ophthalmology, AOU-Careggi, 50234 Florence, Italy
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Novartis (Switzerland) (CH)
- Corresponding author
- Seri, Marco
- Banfi, Sandro
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2021-07-05
- Volume
- 22
- Issue
- 13
- Pages
- 7207
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC8268668
- OpenAlex
- W3177509185
- Cited by
- 47
- References
- 79
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 3 · 2023: 13 · 2022: 10 · 2021: 3
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- inherited retinal disease, retinitis pigmentosa, Leber congenital amaurosis, voretigene neparvovec, gene therapy, genetic diagnosis, pathogenic variant classification, patient selection, next-generation sequencing
- MeSH terms
- Retinoid Isomerohydrolase, Genetic Counseling, Genetic Testing, Genotype, Humans, Mutation, Retinal Diseases, Genetic Variation, Genetic Therapy, Eye Diseases, Hereditary, cis-trans-Isomerases
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