RETINITIS PIGMENTOSA ASSOCIATED WITH THE EYS C2139Y VARIANT : An Important Cause of Blindness in East Asian Populations.

PURPOSE: The study aimed to describe the phenotypic features of retinitis pigmentosa (RP) associated with the previously described EYS C2139Y variant in Singaporeans and establish the importance of this variant as a prevalent cause of RP among East Asians. METHODS: A clinical phenotyping and exome-sequencing study was conducted on consecutive patients with nonsyndromic RP. Epidemiological analysis was performed using Singaporean and global population-based genetic data. RESULTS: A study of 150 consecutive unrelated individuals with nonsyndromic RP found that 87 (58%) of cases had plausible genotypes. A previously described missense variant in the EYS gene, 6416G>A (C2139Y), occurred heterozygously or homozygously in 17 of 150 families (11.3%), all with autosomal recessive RP. Symptom onset in EYS C2139Y-related RP ranged from 6 to 45 years, with visual acuity ranging from 20/20 at 21 years to no light perception by 48 years. C2139Y-related RP had typical findings, including sectoral RP in cases with EYS E2703X in trans . The median age at presentation was 45 years and visual fields declined to less than 20° (Goldmann V4e isopter) by age 65 years. Intereye correlation for visual acuity, fields, and ellipsoid band width was high (r 2 = 0.77-0.95). Carrier prevalence was 0.66% (allele frequency of 0.33%) in Singaporean Chinese and 0.34% in East Asians, suggesting a global disease burden exceeding 10,000 individuals. CONCLUSION: The EYS C2139Y variant is common in Singaporean RP patients and other ethnic Chinese populations. Targeted molecular therapy for this single variant could potentially treat a significant proportion of RP cases worldwide.

When do patients with retinitis pigmentosa present to ophthalmologists? A multi-centre retrospective study.

BACKGROUND: Planned gene therapies for retinitis pigmentosa (RP) depend on viable photoreceptors for efficacy. Understanding disease severity at presentation, and drivers that influence time to presentation is important when planning interventions. We examined features that influence RP severity at initial presentation. METHODS: Multi-centre retrospective cohort study of RP patients at initial presentation. Disease severity was scored using ellipsoid zone (EZ) width on SD-OCT and logistic regression used to determine risk factors for advanced disease at presentation. RESULTS: A total of 146 unrelated RP patients were included. Median age at onset and presentation was 40.5 (range 1-74) and 50.1 (range 3.9-81.8), respectively. Severe disease (<5° of remaining EZ width) was present in 28.1% of cases at presentation. Patients with family history of RP had greater odds of severe disease (OR 3.29, 95% CI 1.56, 6.95; p = 0.002), while male gender, race, age, syndromic features, and socioeconomic status did not. Patients with affected siblings (median EZ width 6.2°; p = 0.01), but not affected parents (median EZ width 9.4°; p = 0.99), presented with severe EZ loss compared to patients without family history (median EZ width 13.1°). Patients with affected siblings had delayed presentation (≥5 years; OR 5.76, 95% CI 1.817, 18.262; p = 0.003) compared to patients without family history. CONCLUSIONS: Family history influences the stage of disease at which RP patients initially seek ophthalmology review. This has implications for patient counselling and the number of patients who may benefit from future therapies.

Diagnostic Challenges in ABCA4-Associated Retinal Degeneration: One Gene, Many Phenotypes.

(1) Purpose: ABCA4-associated retinal degeneration (ABCA4-RD) is a phenotypically diverse disease that often evades diagnosis, even by experienced retinal specialists. This may lead to inappropriate management, delayed genetic testing, or inaccurate interpretation of genetic testing results. Here, we illustrate the phenotypic diversity of ABCA4-RD using a series of representative cases and compare these to other conditions that closely mimic ABCA4-RD. (2) Methods: Genetically confirmed ABCA4-RD cases with representative phenotypes were selected from an inherited retinal disease cohort in Singapore and compared to phenocopies involving other retinal diseases. (3) Results: ABCA4-RD phenotypes in this series included typical adolescent-onset Stargardt disease with flecks, bull's eye maculopathy without flecks, fundus flavimaculatus, late-onset Stargardt disease, and severe early-onset Stargardt disease. Phenocopies of ABCA4-RD in this series included macular dystrophy, pattern dystrophy, cone dystrophy, advanced retinitis pigmentosa, Leber congenital amaurosis, drug toxicity, and age-related macular degeneration. Key distinguishing features that often suggested a diagnosis of ABCA4-RD were the presence of peripapillary sparing, macular involvement and centrifugal distribution, and a recessive pedigree. (4) Conclusions: ABCA4-RD demonstrates a remarkable phenotypic spectrum that makes diagnosis challenging. Awareness of the clinical spectrum of disease can facilitate prompt recognition and accurate diagnostic testing.