This study aims to assess clinical and genetic characteristics as well as the prevalence of inherited retinal dystrophies (IRD) and their subphenotypes in the Finnish founder population. A retrospective analysis of clinical and genetic data from Northern Finnish patients diagnosed with IRD between 1996 and 2023 at Oulu University Hospital, Finland, was conducted. The cohort comprised 582 patients with IRD, categorised into 16 different subphenotypes. Pathogenic or likely pathogenic variants explaining IRD were identified in 36% (n=210/582) of all patients and 80% (n=210/261) of genetically tested patients with IRD. Diagnostic yields varied between different IRD subphenotypes. The genetic aetiology was most commonly confirmed in X-linked retinoschisis, severe early childhood-onset retinal dystrophy, congenital stationary night blindness and choroideremia. The lowest rates of causative variant identification were observed in cone or cone-rod dystrophy and macular dystrophy. In total, 70 pathogenic or likely pathogenic variants were identified across 39 different genes; variants in the FZD4 and RPGR genes were the most prevalent. Over half of the variants were enriched in the Finnish population. The estimated total prevalence of IRDs in Northern Finland was 69.8/100 000 (1:1432). The prevalence of the most common subphenotypes was as follows: retinitis pigmentosa, 25.3/100 000; X-linked retinoschisis, 10.7/100 000; Usher syndrome, 8.9/100 000; choroideremia, 7/100 000 and cone or cone-rod dystrophy, 6/100 000. The Northern Finnish population exhibits an enrichment of population-specific IRD-associated variants, resulting in a high overall prevalence of IRDs and an increased prevalence of selected retinal subphenotypes, such as retinoschisis, choroideremia and Usher syndrome types 3 and 1.

To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.

Significant discoveries in the etiology and pathogenesis of inherited retinal diseases (IRDs) have been made in the last few decades. Of the large number genes that cause IRDs, bi-allelic mutations in RPE65 lead to Leber Congenital Amaurosis type 2 (LCA 2), and can also result in phenotypes described as severe early childhood onset retinal dystrophy (SECORD) and Retinitis pigmentosa 20 (RP20). Following the publication of the successful Phase-III clinical trials of gene augmentation surgery for RPE65-related IRDs with voretigene neparvovec, the FDA approved the commercial use of this pharmacologic agent in December 2017. In this perspective, ongoing and completed gene therapy trials for RPE65-related dystrophies are reviewed and challenges in patient selection, counseling and informed consent, as well as financial considerations of commercial treatment are discussed.

Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention.