To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT). WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs). In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development. We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes. Genet Med 19 4, 412–420.

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

Very short telomere length (TL) provokes cellular senescence in vitro , but the clinical utility of TL measurement in a hospital-based setting has not been determined. We tested the diagnostic and prognostic value of TL measurement by flow cytometry and fluorescence in situ hybridization (flowFISH) in individuals with mutations in telomerase and telomere maintenance genes, and examined prospectively whether TL altered treatment decisions for patients with bone marrow failure. TL had a definable normal range across populations with discrete lower and upper boundaries. TL above the 50 ^th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations in telomere maintenance genes, but the lower threshold for diagnosis was age-dependent. The extent of deviation from the age-adjusted median correlated with the age at diagnosis of a telomere syndrome as well as the predominant complication. Mild short telomere defects manifested in adults as pulmonary fibrosis-emphysema, while severely short TL manifested in children as bone marrow failure and immunodeficiency. Among 38 newly diagnosed patients with bone marrow failure, TL shorter than the 1 ^st age-adjusted percentile enriched for patients with germline mutations in inherited bone marrow failure genes, such as RUNX1 , in addition to telomere maintenance genes. The TL result modified the hematopoietic stem cell donor choice and/or treatment regimen in one-fourth of the cases (9 of 38,24%). TL testing by flowFISH has diagnostic and predictive value in definable clinical settings. In patients with bone marrow failure, it altered treatment decisions for a significant subset.

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.

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.

: 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.