Dorothy T. Wang

While diagnostic disparities by race and age of onset are reported in inherited retinal diseases, their impact on Stargardt disease (STGD)-a clinically and genetically heterogeneous macular dystrophy-remains unclear. We analyzed 246 STGD patients at a U.S. referral center (2003-2024) who completed genetic testing, comparing laboratory-reported results (lab-GT) with manual, phenotype-integrated reinterpretation (m-GT) of ABCA4 sequencing incorporating updated variant databases and genotype-phenotype correlation. Diagnostic yield and variant burden were assessed by race and age of onset. Positive/likely positive (P/LP) lab-GT was identified in 79% (195), with 78% (191) attributable to ABCA4 (ABCA4-positive lab-GT: 57% [141]). M-GT increased ABCA4-P/LP yield to 91% (224). Black participants had lower ABCA4-positive lab-GT than White participants (55% vs. 73%) and fewer pathogenic variants; on multivariable analysis, Black race (OR 0.34) and later age of onset (OR 0.95/year) independently predicted reduced molecular diagnosis. The disparity by race resolved with P/LP m-GT (89% vs. 90%); by age of onset, yield remained lower in late-onset cases (ABCA4-P/LP lab-GT: 86% early- [≤10 yrs], 83% intermediate- [11-44 yrs], 54% late-onset [≥45 yrs], improving to 97%, 94%, and 77% after m-GT). Posttest reinterpretation improves diagnostic yield, particularly for Black and late-onset STGD patients, underscoring the value of ancestry-informed interpretation, historical reanalysis, and genotype-phenotype correlation.

: While diagnostic disparities by race and age of onset are reported in inherited retinal diseases, their impact on Stargardt disease (STGD)—a clinically and genetically heterogeneous macular dystrophy—remains unclear. We analyzed 246 STGD patients at a U.S. referral center (2003-2024) who completed genetic testing, comparing laboratory-reported results (lab-GT) with manual, phenotype-integrated reinterpretation (m-GT) of ABCA4 sequencing incorporating updated variant databases and genotype-phenotype correlation. Diagnostic yield and variant burden were assessed by race and age of onset. Positive/likely positive (P/LP) lab-GT was identified in 79% (195), with 78% (191) attributable to ABCA4 ( ABCA4- positive lab-GT: 57% [141]). M-GT increased ABCA4- P/LP yield to 91% (224). Black participants had lower ABCA4- positive lab-GT than Whites (55% vs. 73%) and fewer pathogenic variants; on multivariable analysis, Black race (OR 0.34) and later age of onset (OR 0.95/year) independently predicted reduced molecular diagnosis. The disparity by race resolved with P/LP m-GT (89% vs. 90%); by age of onset, yield remained lower in late-onset cases ( ABCA4- P/LP lab-GT: 86% early-[≤10yrs], 83% intermediate-[11-44yrs], 54% late-onset [≥45yrs], improving to 97%, 94%, and 77% after m-GT). Post-test reinterpretation improves diagnostic yield, particularly for Black and late-onset STGD patients, underscoring the value of ancestry-informed interpretation, historical reanalysis, and genotype-phenotype correlation.

Importance: Multiple clinical trials for Stargardt disease are ongoing, as there is no treatment available for this condition. However, timely recruitment of clinical trial participants remains challenging, risking incomplete study cohorts and prolonged study timelines that together escalate the possibility of trial failure. Factors associated with clinical trial participation in Stargardt are poorly understood. Identifying drivers of clinical trial participation and genetic testing completion may improve trial design and access. Objective: To identify demographic and clinical factors associated with clinical trial participation and genetic testing completion in Stargardt. Design: Retrospective cohort study of patients seen at a genetic eye disease center from January 2003 to December 2024. Associations were evaluated using bivariate analysis and multivariable logistic regression. Setting: Single-center study at a tertiary referral center. Participants: 280 patients clinically diagnosed with Stargardt disease [median (IQR) age at presentation 37 (20-52) years; follow-up 4.5 (1.6-10.1) years]. Exposures: Demographic and clinical factors, including race, insurance, education, employment, parenting status, age of onset, and genetic counseling history. Main Outcomes and Measures: Genetic testing completion (all participants) and clinical trial participation (among ABCA4- positive participants). Results: Among 280 participants, 246 (88%) completed genetic testing. Among 223 ABCA4 -positive participants, 45 (20%) had enrolled in a clinical trial. Clinical trial participation was associated with later onset [≥60 years; OR (95% CI) 36.7 (2.5-537.1)], part-time employment [9.3 (1.01-172.9)], and was less likely among retired individuals [0.014 (0.0005-0.4)] or those without genetic counseling [0.22 (0.07-0.71)]. In multivariable analysis, genetic testing completion was less likely in participants who were Black [0.40 (0.16-0.98)], under/uninsured [0.47 (0.19-0.97)], without genetic counseling [0.09 (0.03-0.22)], or not planning to have children [0.35 (0.14-0.89)]. Common reasons for non-completion included loss to follow-up, refusal, and awaiting genetic counseling. Conclusions and Relevance: In this large single-center cohort, one in five participants with molecularly confirmed Stargardt had enrolled in a clinical trial. Older age of onset, part-time employment, and genetic counseling may promote clinical trial participation among Stargardt patients, while retirement may be negatively associated. These findings may ultimately support the development of rational strategies to accelerate clinical trial enrollment, thereby broadly supporting the development of effective treatments for Stargardt disease.

Objective: To identify clinical and demographic predictors of genetic testing (GT) completion and diagnostic yield among patients with genetic eye disorders (GED) at a large U.S. tertiary academic center. Design: Retrospective cohort study. Participants: Patients with clinically diagnosed GEDs evaluated at the Wilmer Eye Institute’s Genetic Eye Disease (GEDi) Center between 2002 and 2025. Methods: Demographic, clinical, and GT data were extracted. Bivariate analyses and multivariable logistic regression identified factors associated with GT completion and molecular diagnosis. Subgroup analyses examined racial disparities between Black, non-Hispanic White, and Other race participants. Main Outcome Measures: Proportion of patients completing GT, molecular diagnostic yield, and clinical/demographic predictors of each. Results: Of 1466 participants (median age at presentation 44 years, symptom onset 28 years; median follow-up 6 years), 74% (1088) completed genetic testing, with a likely molecular diagnosis achieved in 62%, inconclusive results in 22%, and no diagnosis in 16%. GT completion was more likely among younger participants with earlier symptom onset, and longer follow-up. Likely molecular diagnosis was more likely in participants with earlier symptom onset, worse visual acuity (VA), male sex, and syndromic or X-linked phenotypes. Black and Other race participants had significantly lower odds of completing GT (Black: OR [95% CI] 0.40 [0.30-0.53]; Other: 0.57 [0.36-0.92]) and receiving a likely molecular diagnosis (Black: 0.37 [0.26-0.51]; Other: 0.58 [0.35-0.98]), and consistently exhibited worse VA at both baseline and follow-up. Notably, among Black and Other race participants, disparities in GT completion and visual outcomes persisted despite equivalent or shorter time from presentation to GT completion, suggesting barriers arise independently of delays in care engagement. We identified 118 causative genes among participants with likely molecular diagnoses, with ABCA4 , USH2A , PRPH2 , RHO , and BEST1 accounting for 47% of cases. Conclusions: This is the largest single-center GED genetic testing cohort reported in the U.S. and reveals significant disparities in GT completion and yield by race, age, sex, and disease-level factors. Our findings underscore the need to expand early access to GT, diversify genomic databases, and address systemic barriers to ensure equity in GED diagnosis, clinical trial access, and delivery of emerging therapies.

Despite efforts to improve global access to basic ophthalmologic services, there remains a paucity of data regarding the prevalence of untreated ocular disease among forced migrants and refugees, particularly in east Africa. We aimed to estimate the prevalence of untreated and surgically amenable eye conditions among refugees in Nyarugusu Refugee Camp, Tanzania, and to identify factors associated with untreated eye problems. We conducted cluster-randomized sampling using the cross-sectional Surgeons OverSeas Assessment of Surgical Needs (SOSAS) survey tool to assess prevalence of surgical eye disease and access to health services among refugees in Nyarugusu from August-September 2021. Descriptive analysis and multivariable logistic regression were performed to explore associations between covariates and the presence of unresolved eye problem(s). Among 3574 refugees, 12% (n=430; mean age 36±20 yrs.) reported eye issues. Of these, 296 (69%) further characterized their problems, with 44% reporting acquired disability and 42% non-injury-related wounds. Of the 368 (86.4%) who described their issues as disabling, 78.8% endorsed a negative impact on ability to work and 27.7% required help with daily living. Most were currently (84.6%; 357/427) and chronically affected (>12 months; 88.3%; 378/428). Farming and housewife occupations were positively associated with unresolved eye problem(s). Among 312 (72.7%) who sought care, only 13 (4.2%) underwent surgery. Nearly half (136) of 279 surveyed individuals self-reported potential surgical needs, citing barriers to surgical care such as lack of available services, financial and time constraints, and limited knowledge about accessing treatment. In conclusion, nearly 1 in 8 refugees endorsed chronic and disabling eye problems, negatively impacting their work and daily life. Most who may benefit from surgery have not received care due to significant barriers and gaps in ophthalmologic services. Further investigation to better characterize specific ocular etiologies in under-resourced protracted refugee settings can inform resource allocation strategies to address unmet eye care needs.

A maternal high-fat diet is associated with reduced oocyte quality, fertilization, as well as altered preimplantation embryo development. It is unclear, especially in women, if these effects are due to the diet itself or the subsequent development of metabolic dysfunction. Thus, a longitudinal study was performed using the clinically relevant rhesus macaque model to test the hypothesis that short-term exposure to a high-fat Western Style Diet (WSD) negatively impacts primate ovarian follicle, oocyte, and preimplantation embryo development. Oocytes were collected from regularly cycling female rhesus macaques (N=10; ages 5-6yrs) after undergoing a controlled ovarian stimulation protocol (COS1) while consuming a Standard Chow Diet (SCD; 13% fat). Animals were then switched to WSD (35% fat) for 6-8 months prior to going through a second COS protocol (COS2). Follicular fluid (FF) was collected from 4 individual follicles per female per COS and pooled for subsequent steroid and cytokine analysis by mass spectrometry and a multiplex assay system (Luminex), respectively. Individually isolated oocytes and oocytes aspirated from the remaining follicles were then assessed for reinitiation of meiosis, in vitro fertilization (IVF) and subsequent blastocyst formation rates. Time-lapse monitoring (TLM) was performed post-IVF to study initial mitotic division kinetics, as well as cellular fragmentation and multipolar divisions. Weight gain by the female macaques post-WSD intake recorded at COS2 was significant (P=0.0001), but insulin resistance (HOMA-IR) at the time of COS2 was not significantly different from COS1. Of the 10 females, 2 were resistant to weight gain and another 2 did not respond to COS2. Excluding the 2 non-responsive females, FF interleukin (IL)-1 receptor antagonist (IL-1RA; P=0.009) and IL-2 (P=0.004) levels decreased post-WSD intake. The levels of cortisone, an inactive metabolite of the biologically active glucocorticoid cortisol, were 18% higher, while mean cortisol levels were 22% lower, in the FF collected from COS2 relative to COS1. This resulted in a reduced cortisol:cortisone ratio post-WSD intake (P=0.028) and negatively correlated with the resident oocyte’s ability to form a blastocyst following IVF (R=-0.66; P<0.05). While 138 blastocysts were obtained from COS1, the total number blastocysts collected from COS significantly decreased to 77 (P=0.036) post-WSD intake (COS2). Lastly, a higher occurrence of multipolar divisions was observed with fertilized oocytes collected post-WSD diet consumption (COS2) compared to fertilized oocytes collected from animals receiving SCD (COS1). These results demonstrate that WSD consumption alters the intrafollicular microenvironment as well as oocyte and preimplantation embryo development in non-human primates even in the absence of large-scale metabolic changes. Funding: NIH P51 OD011092, NCTRI P50 HD071836