Carolyn Applegate

Background: Genetic testing for inherited cardiovascular conditions is recommended by multiple national guidelines to inform medical management. However, access to genetic counseling and testing is often limited particularly in the inpatient setting. Cardiologists cite lack of access to genetic counselors as a reason for not pursuing genetic testing. Genetic test education videos have been successfully implemented in the outpatient setting to increase patient volumes and decrease wait times, but they have not been studied in the inpatient setting. Methods: This was a pilot study utilizing a genetic test education video in lieu of a traditional genetics consult for inpatients with a suspected hereditary cardiomyopathy, arrhythmia or familial hypercholesterolemia. Patients completed the cardiovascular multidimensional model of informed choice (MMIC) and SURE scales to assess whether the video provided sufficient information to make an informed decision. Results: Over 22 months, 186 adult cardiovascular inpatients at Johns Hopkins Hospital were referred with 112 patients consenting to the study. Implementation of the pre-test videos increased the average number of monthly consults from 1 to 8. After watching the video, 90% (100/111) of patients made an informed choice to proceed with genetic testing using the MMIC scale. Using the SURE scale, 87% (97/112) of patients had no decisional conflict regarding whether or not to proceed with genetic testing. Conclusions: These results indicate a pre-test genetic educational video could be considered as a strategy to scale access to genetic counseling and cardiovascular genetic testing, especially in hospital systems where access to genetics is limited in the inpatient setting.

Background: Pretest genetic counseling (GC) is recommended in conjunction with genetic testing (GT) for cardiovascular (CV) indications, yet access to CVGC is limited leading to delayed GT. Posttest GC could increase GC and GT access but requires efficient pretest education that supports both informed GT decision-making and robust GT uptake. Methods: We developed four indication-tailored online CV genetics education videos and deployed them in a 3-arm randomized trial comparing pretest vs. posttest outpatient CVGC (RESEQUENCE-GC, NCT05422573 ). Participants were 1:1:1 randomized to pretest video education plus an optional (efficiency arm) or required (flipped arm) phone call with a genetic counselor and planned posttest CVGC or to standard pretest CVGC (SOC arm). Questionnaires administered at baseline and post-education included the CV Multidimensional Model of Informed Choice [MMIC] to quantify GT knowledge and informed GT choice. Results: 389/767 (50.7%) adults aged 18-80 (mean 51.2±14.9 years) scheduling a first CVGC appointment consented to RESEQUENCE-GC and completed the baseline questionnaire. Efficiency arm participants (video education + optional phone call) were most likely to complete pretest education (134, 97.4% efficiency; 107, 85.6% flipped; 111, 87.4% SOC, p=0.0012) and elect GT (131, 95.6% efficiency; 105, 84.0% flipped; 107, 84.2% SOC, p=0.0036). Few (4, 2.9%) efficiency arm participants requested an optional pretest phone call. Most flipped arm participants (90, 84.1%) had no post-video questions, consistent with the 97 second [IQR: 65s-145s] median call duration. CV genetics knowledge was high post-education (median 8 [IQR 7,8]/8 MMIC items correct). Only video-based pretest education was associated with a significant increase in knowledge (p<0.0001). Nearly all participants made an informed GT choice with no difference between intervention (95.6%) and SOC (90.4%) arms (p=0.074). Conclusions: Tailored, online video pretest education can enhance CV GT uptake, support informed GT decision-making, and be integrated into efficient pretest workflows, suggesting utility in scalable posttest CVGC.

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.

This series reports 3 unrelated individuals with features of neurofibromatosis type 1 (NF1) and/or schwannomatosis (SWN) in whom variants of uncertain significance (VUSs) were resolved through RNA testing and tissue analysis, highlighting the clinical impact of these tests. Each patient's genetic testing identified a VUS that could have explained their clinical presentation. Because diagnostic criteria were not met, we performed VUS resolution. For patient 1, we conducted tissue analysis and RNA-based Sanger sequencing. For patients 2 and 3, RNA-based Sanger sequencing was pursued. Tissue analysis and RNA testing reclassified the NF1 c.8050 + 93A>T VUS in patient 1 as pathogenic, confirming diagnosis of NF1. RNA testing of the NF2 c.448-5T>C VUS in patient 2 reclassified the variant as likely benign, ruling out diagnosis of germline neurofibromatosis type 2 (NF2). RNA testing of the SPRED1 c.377-13T>A VUS in patient 3 reclassified the variant as likely benign, ruling out diagnosis of germline Legius syndrome. Because diagnostic criteria for NF1 and SWN include genetic testing, resolving VUSs in those who do not meet criteria is crucial for clinical care. In this article, we report 3 cases in which RNA testing and tissue analysis clarified pathogenicity of VUSs, thereby affecting clinical care, and in one case providing a definitive diagnosis.

: 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.

Purpose: Whole exome or genome sequencing (WES and WGS, respectively) can be valuable in identifying the molecular basis of inherited retinal disorders (IRD), particularly when panel-based testing yields negative or inconclusive results. However, WES or WGS may reveal secondary findings (SF) associated with severe diseases such as cancer, neurodegenerative and cardiovascular conditions. The American Society of Medical Genetics and Genomics has defined a list of reportable SFs that entail significant health implications. Acknowledging the limited awareness of SFs among ophthalmologists, we sought to understand the frequency, characteristics, and impact of SF following WES/WGS. Design: Retrospective cross-sectional study Subjects, Participants and/or Controls: We included patients with suspected IRD who underwent WES or WGS at Johns Hopkins Hospital from 2019-2024. WES/WGS was ordered following genetic counseling and consenting by certified genetic counselors (CGCs). Methods/ Main Outcome Measures: We conducted a qualitative analysis of WES/WGS indications and SF. We also analyzed SF consent status and recommended clinical actions. Results: The study included 36 patients, 50% of whom were females. 34 patients received WES, and two received WGS. The mean age was 45 ± 24 years. 89% (32/36) patients consented to examine SF, while 11% declined analysis. Of the 32 patients who consented to SF analysis, 5 had SFs (16%). Detected SF included pathogenic or likely pathogenic variants in the APC, RET, TP53, MUTYH, and BRCA2 genes associated with familial adenomatous polyposis, multiple endocrine neoplasia, Li-Fraumeni syndrome, MYH -associated polyposis, and hereditary breast and ovarian cancer, respectively. After WES/WGS, patients were advised to continue managing their symptoms with their healthcare team, take further medical actions, and/or encourage family members to pursue SF genetic testing. Of the 33 individuals who received post-test genetic counseling, 79% (26/33) were counseled by a CGC, 18% (6/33) by an ophthalmologist, and 3% (1/33) by a primary care provider. IRD gene results were positive in six (16%) patients, none of whom had SF. Conclusions: SF are not infrequent when pursuing WES/WGS for diagnostic testing in IRDs. This study highlights the need for ophthalmologists to be prepared to discuss and manage SF. Multidisciplinary care, including a CGC, enables successful clinical management in this context.