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Aberrant dopaminergic signaling is implicated in the core symptoms of attention deficit hyperactivity disorder (ADHD), including dysregulated attention, impulsivity, and hyperactivity. In a mouse model with disrupted scaffolding motif of the dopamine transporter (DAT-AAA), we previously reported extensive loss of DAT expression in striatum, resulting in locomotor hyperactivity, dysfunctional reward-driven motivation, and attenuated behavioral response to amphetamine compared to wildtype (WT) controls. Here, we investigated attention and impulsivity in DAT-AAA mice using the 5-choice serial reaction time task (5-CSRTT). Baseline task acquisition was established using a 2-s stimulus duration (SD) and fixed 5-s intertrial interval (ITI). A variable SD probe (0.2-1.8&#xa0;s with fixed 5-s ITI) was then used to challenge attentional performance and enable Theory of visual attention (TVA)-based modeling. Finally, a variable ITI schedule randomized to 5-, 10-, or 15-s ITI with fixed 2-s SD for 15 consecutive training days probed impulsive action. Training revealed higher rates of premature responding (p&#xa0;<&#xa0;0.05) in DAT-AAA mice, a finding confirmed in the variable ITI challenge (p&#xa0;<&#xa0;0.05). DAT-AAA mice demonstrated inattention (p&#xa0;<&#xa0;0.001) in the variable SD test, and TVA-based modeling revealed a specific deficit in visual processing speed (p&#xa0;<&#xa0;0.01). Finally, increased anxiety-related behavior was seen in the open field test. These preliminary findings suggest that reduced DAT expression in striatal terminals is associated with inattentive and excessive impulsive behaviors, supplementing our previously reported locomotor hyperactivity finding. The DAT-AAA mouse therefore shows face validity in terms of inattention, impulsivity, and hyperactivity, and may be a new model to study the neurobiology of ADHD.

BACKGROUND: Predicting in vitro fertilization (IVF) pregnancy outcomes is crucial for individualized decision-making. However, due to complex interactions among multiple factors, accurate manual integration and assessment are challenging. This study aims to develop an interpretable machine learning (ML) model for predicting the probability of clinical pregnancy after fresh and frozen-thawed embryo transfer. METHODS: This retrospective study included infertile patients undergoing fresh or frozen-thawed embryo transfer between December 2023 and June 2025. Endometrial regions of interest (ROIs) were manually segmented on mid-sagittal uterine ultrasound images. The K-means clustering algorithm was employed to partition the ROIs into habitat subregions. Radiomic features were extracted from the entire ROI and each subregion. After feature selection using Mann&#x2013;Whitney U tests, Pearson correlation, and mRMR, 11 machine learning algorithms were trained in combination with clinically independent predictors. Model hyperparameters were optimized through five-fold stratified cross-validation and grid search. The optimal classifier was selected based on performance evaluation to construct the final predictive model, subsequently validated on an independent test set. Shapley Additive Explanations (SHAP) provided model interpretability. RESULTS: This study included 543 patients, randomly divided into a training cohort of 380 and a test cohort of 163. ROIs were subdivided into four habitat subregions. Imaging features were systematically extracted from the entire ROI and each subregion. Following mRMR, 15 habitat subregion features were incorporated into the model. Based on area under the ROC curve, the ExtraTrees model demonstrated optimal predictive performance on the test set (AUC: 0.766; 95% CI: 0.689&#x2013;0.830; accuracy: 0.699; sensitivity: 73.9%; specificity: 65.3%; F1 score: 0.726). SHAP analysis confirmed the significant contribution of embryo type and higher-order texture features from specific subregions to model prediction. CONCLUSION: A habitat-based radiomics machine learning model integrating endometrial ultrasound features and clinical data effectively predicted clinical pregnancy outcomes following embryo transfer. This approach offers a non-invasive, interpretable tool with potential to support personalized embryo transfer strategies in assisted reproduction.

H5 subtype avian influenza virus (AIV) can infect both chickens and ducks, leading to substantial economic losses. Nevertheless, certain strains cause silent infections in ducks. In this study, a goose-origin clade 2.3.4.4h H5N6 AIV was isolated, which caused high mortality in mixed-gender white leghorn chickens but no deaths in mixed-gender mallard ducks. After independent serial in vitro passage in duck embryo fibroblasts (DEFs) and in vivo passage in specific-pathogen-free (SPF) ducks, the DEF-passage 10 (P10) virus induced markedly higher mortality rates and viral loads in SPF ducks compared to the DEF-P1 virus and the original parental virus prior to passage. Similarly, the in vivo-passaged P3 and P4 viruses exhibited significantly higher mortality rates than the P1 virus in SPF ducks, with 100% mortality and markedly increased viral titers in the organs. A whole-genome SNP analysis identified seven high-frequency mutations in the M1, NA and NS1 proteins. The NS1-F161L substitution virus exhibited significantly increased mortality rates, viral loads in multiple tissues, and a robustly induced innate immune response in ducks. Furthermore, dynamic evolutionary variations in the NS1 protein among global H5 avian influenza viruses revealed that the NS1-F161L substitution became dominant in clade 2.3.4.4b viruses in 2021 and subsequent years. Collectively, our findings demonstrate that host-driven adaptation can rapidly increase the pathogenicity of H5N6 AIVs in ducks and identify NS1-F161L as a critical virulence marker. These results offer novel insights relevant to the molecular surveillance, virulence prediction, and risk assessment of circulating H5 AIVs in waterfowl.

Quantitative, spatially resolved analysis of gene expression is essential for assessing cell-type-specific molecular profiles. In the Drosophila visual system, extensive genetic tools open a framework for direct evaluation of both RNA and protein levels in defined neuronal populations. Here, we present a step-by-step protocol that combines expansion-assisted HCR-smFISH (hybridization chain reaction single-molecule fluorescence in situ hybridization) with immunohistochemistry to enable quantitative analysis of cell-type-specific molecular profiles&#xa0;in genetically defined visual system neuronal types. The workflow is optimized for cells labeled with nuclear-localized or membrane-bound markers, allowing measurement of transcript and protein levels in the same neurons. Following tissue expansion, samples are imaged using light-sheet microscopy for rapid volumetric acquisition, with an alternative mounting and imaging workflow demonstrated for standard inverted laser scanning and spinning disc confocal microscopes. We further provide an automated segmentation algorithm that distinguishes nuclear and cytoplasmic transcripts, enabling analyses of transcriptional state and subcellular RNA localization. Practical guidance is provided on experimental parameters and common pitfalls affecting signal quality, tissue integrity, and quantitative performance. Representative applications include validation of cell-type-specific RNA interference by quantifying corresponding changes in RNA and protein levels. By enabling integrated RNA- and protein-level measurements with cell-type specificity, this approach provides a scalable strategy for hypothesis-driven molecular analysis and, in targeted contexts, a practical alternative to single-cell transcriptomic assays. This protocol provides a practical approach for validating cell-type-specific molecular perturbations while preserving the anatomical context of the intact Drosophila brain.

Lynch-like syndrome (LLS) is associated with an incomplete understanding of its molecular basis. Some LLS tumors harbor somatic variants in mismatch repair genes, whereas germline variants in other DNA repair genes point to a hereditary predisposition in certain cases. Clinically, LLS patients tend to develop colorectal cancer (CRC) earlier, have a stronger family history of CRC, and respond better to immunotherapy compared with sporadic CRC cases. This study seeks to identify cancer-susceptibility genes in LLS patients, which could affect diagnosis, treatment, and surveillance. Germline exome sequencing was performed on 102 participants, including 14 previously reported cases. In vitro models were created to study the effect of loss-of-function (LoF) variants in DNA repair genes. Gene/protein expression was evaluated using quantitative real-time PCR and Western blotting, and DNA repair capacity was assessed via H2AX phosphorylation after ionizing radiation exposure. Nine rare LoF variants were identified in DNA repair genes, including 3 in RecQ DNA helicases (WRN HGNC:12791, RECQL5 HGNC:9950). LLS patients had a higher mutational burden in DNA repair genes across various cancer phenotypes. In vitro, cells with these LoF variants showed reduced gene-protein expression and increased H2AX phosphorylation after irradiation, indicating impaired DNA repair. A single LoF variant in RecQ DNA helicase genes can result in significant DNA repair deficiency, leading to genomic instability and contributing to CRC development in LLS. Therefore, we present evidence for incorporating RECQL5 into genetic testing panels for CRC risk assessment, which would enhance both diagnosis and treatment outcomes.

Precise genome editing remains a major challenge in functional genomics, particularly for generating knock-in (KI) alleles in model organisms. Here, we introduce the mini-golden system, a versatile Golden Gate-based subcloning platform that enables rapid assembly of donor constructs containing homology arms and a gene of interest. This system offers a library of middle entry vectors including diverse genes, enhancing the preparation of donor minicircles for KI applications. Using the mini-golden system, we efficiently generated a foxd3CreER KI zebrafish line, allowing conditional recombination in neural crest cells. To further improve genome editing precision, we developed a synthetic exon-based donor template strategy combined with fluorescence screening. Using this approach, we successfully engineered a targeted isoleucine-to-valine substitution (Ile-to-Val) in hbaa1.2, one of the two adult hemoglobin alpha genes in zebrafish. Importantly, despite the high sequence similarity between hbaa1.2 and its paralog hbaa1.1, our strategy specifically edited hbaa1.2, demonstrating the effectiveness of the synthetic exon approach. This method minimized undesired recombination and significantly improved the identification of lines carrying the edited genome. Together, we provide a robust toolkit for efficient and precise genome engineering in zebrafish, with broad applicability to other model systems.

Although RNA analysis holds potential to increase the diagnostic yield of exome sequencing (ES) for rare disease, its practical utility and barriers to its large-scale implementation have not been well studied. To quantify the impact of RNA analysis in clinical ES, we retrospectively assessed variants reported over a nearly 5-year period at a single clinical laboratory. Reported variants and corresponding genes were assessed based on 4 eligibility criteria for RNA analysis at our laboratory: (1) suspected spliceogenic impact, (2) sufficient gene expression in blood, (3) characterized gene with at least moderate gene-disease validity, and (4) mechanism of disease is loss of function (LOF). A total of 1987 unique variants were reported on ES during the study period. In total, 11.4% (226/1987) were putative splicing variants, 68.2% (1355/1987) had sufficient gene expression in blood, 83.0% (1650/1987) were in a gene with a LOF mechanism, and 98.9% (1965/1987) occurred in characterized genes. When assessed on the 4 criteria combined, 7.6% (152/1987) of variants were eligible for RNA analysis. Of those variants, which were identified in 153 individuals, 35.5% (54/152) were variant of uncertain significance (VUS), representing 5.2% (54/1035) of all VUS reported. Nine cases were successfully recruited for retrospective RNA analyses, 7 of whom had VUS and 2 who had a likely pathogenic variant. Of the VUS, 71.4% (5/7) were upgraded, whereas 28.6% (2/7) remained a VUS. The 2 likely pathogenic variants remained likely pathogenic. These findings indicate that putative splicing variants represent a substantial portion of VUS in this clinical ES cohort, and most were identified in characterized LOF genes with RNA expression in blood. Integrating RNA analysis with clinical ES could clarify over 5% of reported VUS, even when accounting for known limitations in a rare disease setting, making it a viable strategy to increase diagnostic accuracy and the likelihood that a patient will receive a clinically meaningful report.

Workplace genetic testing (wGT) is a wellness benefit offered to employees, providing a new access point for genetic testing. Although genetic counseling is not typically required in wGT, genetic counselors (GCs) play a key role in integrating genetic testing into health care and may interact with wGT in industry, laboratory, or clinical settings. To ascertain US GCs' perspectives and experiences with wGT, we administered a web-based survey, targeting GCs most likely to have professional experience with wGT. Descriptive statistics were used to characterize responses. Of n = 331 participants (mean age = 36, >80% White female), 27.0% reported having professional experience with wGT. Over half (62.4%) were open to providing counseling on wGT. Most (92.7%) expected wGT to increase genetic testing access, especially for those not meeting clinical criteria (94.8%), but 59.4% expected wGT to increase genetic discrimination. The majority (69.2%) agreed employers should be permitted to offer wGT but disagreed with employers selling (90.9%) and accessing (68.3%) employees' aggregate data. GC participants demonstrated qualified support for wGT and favored limited employer access to, and use of, employees' wGT data. As genetic testing avenues expand, these findings can inform the effective implementation of wGT and testing in nonclinical settings.

Genome sequencing (GS) presents a powerful approach to uncover disease-causing genetic variants. We used GS to examine single vs dual molecular causes in some of the most complicated pediatric cases-those with both a neoplasm and a birth defect. From our pediatric biobank, we selected 1463 children with a major congenital malformation, such as cleft lip/palate or internal organ defect, including 827 cases with a pediatric-onset cancer. The cohort includes nearly 40% non-White and/or multiracial individuals. We implemented GS as a first-tier diagnostic method and hypothesized that in most cases, a single disease-causing variant would explain their complex disease pictures. We developed a novel variant annotation and prioritization algorithm to provide a molecular diagnosis. Our algorithm uncovered 361 disease-causing single-nucleotide variants/insertion/deletions in patients with compatible phenotypes (n = 324/1373; 23.6%), including 207 known and 120 novel variants in 167 genes. In addition, we identified aneuploidies (n = 41; 3%) and disease-causing copy-number variations, including haploinsufficient regions, de novo pathogenic variants and variable degrees of mosaicism (n = 65, 4.7%). Likely deleterious variants were identified in 2 candidate genes, GNG13 and RTKN2. Most cases had a single molecular cause for the cancer and the congenital anomaly, with notable exceptions of dual molecular causes. In children with severe and complex phenotypes, our findings demonstrate that GS revealed causative molecular underpinnings, including novel causes. A single genetic defect may underlie phenotypes of high complexity that appear unrelated, with double molecular findings identified in the same patient on rare occasions.

Medical genetic services remain limited in low- and middle- income countries, such as Nepal, leading to poor health outcomes for individuals affected by genetic disorders. This study aimed to assess perspective and characterize current practices and attitudes toward genetic services among health care providers in Nepal. A web-based survey was completed by 131 clinicians across multiple disciplines, exploring participant demographics, experience with genetic services, and perceived barriers to genetic testing and counseling. Although 42% of respondents reported regularly caring for patients with suspected genetic disorders, 77% of providers reported difficulties with obtaining genetic testing. The most frequently cited barriers included limited laboratory availability (28%), cost (26%), and logistical challenges (19%). Many respondents reported confidence in discussing disease recurrence risk (63%), treating genetic disorders (40%), and providing genetic counseling (48%), and the majority (86%) expressed interest in furthering their genetic education because only 19% felt their current genetics knowledge was sufficient. This study highlights a clear demand for accessible, affordable, in-country genetic services in Nepal and underscores the need for investment in clinical training and capacity building to improve access and outcomes for patients with genetic disorders.

We developed a genome sequencing-based test (Rapid Targeted Analysis of the Genome for Infants [rTAG-I]) to minimize turnaround time while maximizing diagnostic yield and access to rapid sequencing for critically ill infants. We sought to create a system of predicting which infants would have a molecular finding. We performed a prospective observational study of infants referred for genetics consult who received rTAG-I testing, which analyzes 3183 curated genes with phenotype-agnostic prioritization of pathogenic and likely pathogenic variants. Infants were stratified by perceived likelihood of a diagnostic result and divided into "Likely," "Uncertain," and "Not Likely." We also assessed whether reportable findings correlated with patient phenotypes. We identified reportable findings in 133/400 (33%) infants. Access to rapid testing increased from 1% to 20% of all infants hospitalized in the neonatal/infant intensive care unit and cardiac intensive care unit, with a median turnaround time of 4.9 days. rTAG-I performed as well as exome/genome sequencing. Clinically associated results were identified in 59% of the "Likely" group and 9% of the "Not Likely" group. rTAG-I produced a high rate of reportable findings with a rapid turnaround time. Our ability to predict infants who would benefit most was imperfect, reinforcing that broad access to genome-based testing is still required.

Delayed diagnosis of Mendelian disease prevents early therapeutic intervention that could improve symptoms and prognosis. One major contributing challenge is functional interpretation of noncoding variants that alter splicing. Here, we aimed to better understand both how splice altering variants contribute to Mendelian disease and how to identify such mechanisms via an instrumental case study of 2 siblings with glycogen storage disease (GSD) IX &#x3b3;2. The siblings had a classic clinical presentation, enzyme deficiency, and a known pathogenic splice variant on 1 allele of PHKG2 (HGNC:8931). Despite the autosomal recessive nature of the disease, no coding variant on the second allele was identified by targeted sequencing. We evaluated potential noncoding pathogenic variants using genome sequencing and RNA sequencing and created an isogenic model of the candidate variant using CRISPR/Cas9 genome editing. In both siblings, we identified a second variant (NC_000016.10:g.30754626T>G [GRCh38]): a deep intronic variant that caused a 76-bp pseudoexon inclusion in PHKG2. In a HEK293T cell model in which we installed that variant, we confirmed its effects on splicing in addition to multiple biochemical and cellular phenotypes consistent with GSD IX. We then reversed aberrant splicing using antisense oligonucleotide technology. As evidenced by RNA sequencing, population and allelic segregation data, and phenotyping of an isogenic cell culture model of the variant, we concluded that PHKG2 c.556+1069T>G causes GSD IX &#x3b3;2 and can be targeted using antisense oligonucleotides. This demonstrates a novel and robust pathway for detecting, validating, and reversing the impacts of noncoding causes of rare disease.

Ring chromosomes (RCs) are rare cytogenetic abnormalities involving copy-number variants and chromosome instability. Identifying the breakage-fusion sequences of RCs at nucleotide-level resolution can elucidate the cytogenomic rearrangements and ring formation mechanisms. This study used short-read genomic sequencing (srGS) and long-read genomic sequencing (lrGS) alongside the telomere-to-telomere reference genome to characterize the breakage-fusion events of 17 RC cases. Complete RCs without loss of euchromatin by a fusion of subtelomeric or telomeric regions were noted in a RC14 and a RC20. Incomplete RCs with intrachromosomal copy-number variants were noted in 15 cases, including a RC3, a RC4, 4 RC13s, a RC14, 3 RC18s, a RC21, 3 RC22s, and an RCY. srGS defined breakage-fusion sequences in single-copy sequences, and lrGS mapped subtelomeric and pericentric repetitive sequences using the telomere-to-telomere reference genome. The breakage-fusion sequences revealed ring formation mechanisms by intrastrand nonhomology end joining in 5 RCs, microhomology-mediated end joining in 8 RCs, and microhomology-mediated break-induced replication in 4 RCs. This study demonstrated the analytic validity and diagnostic utility of srGS and lrGS in delineating the genomic rearrangements in RCs for better interpreting clinico-cytogenomic correlations and further analysis of RC behavior in cell cycles.

Pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in dysfunctions of the CFTR protein, leading to cystic fibrosis (CF). This genetic disorder is characterized by severe symptoms in the respiratory and digestive systems.Currently, highly effective CFTR modulator treatments, such as the Elexacaftor-Tezacaftor-Ivacaftor combination, may represent the primary therapeutic option for approximately 82% of people with cystic fibrosis who have at least 1 F508del variant. However, the remaining 18% with rare CFTR variants, including nonsense variants, often lack access to these therapies. Nonsense variants lead to nonfunctional CFTR proteins and contribute to more severe CF symptoms. Research efforts focus on understanding the effects of these variants on disease severity and response to treatment. This study utilizes patient-derived intestinal organoids to evaluate the recovery of CFTR function in cells with nonsense variants. Specifically, we tested 3 translational readthrough-inducing molecules: NV848, NV914, and NV930. Our studies highlighted the positive effect of NV848 on patient organoid swelling, improving CFTR channel function, whereas NV914 and NV930 did not induce organoid swelling, similar to PTC124 treatment. In conclusion, this study highlights the potential of translational readthrough-inducing molecules to restore CFTR function in cells with nonsense variants. By leveraging patient-derived intestinal organoids, our findings showed that NV848, in combination with Elexacaftor-Tezacaftor-Ivacaftor and the nonsense-mediated mRNA decay inhibitor NMDI14, enhances CFTR activity. This contributes to the development of personalized therapies for individuals with rare CFTR variants, addressing a critical unmet need in cystic fibrosis treatment.

BackgroundSerotonin (5-hydroxytryptamine, 5-HT) is essential to mood regulation, and its dysfunction has been strongly connected to depression and anxiety disorders. The key enzyme for serotonin production is tryptophan hydroxylase 2 (TPH2); genetic abnormalities influencing TPH2 activity have been connected to mood disorders.ObjectiveOur study aims to understand the consequences of human TPH2 mutation-TPH2 R439H in mice, especially depression and anxiety-like behaviors.MethodsCompared to wild-type, we employed 6-month-old knock-in mice, heterozygotes (one allele) and homozygotes (two alleles) expressing TPH2 R439H analogous to the human R441H TPH2 mutation. We examined behavioral differences between TPH2-KI and WT mice, heterozygotes and homozygotes, and males and females. Tail suspension and forced swim assessed depression-like behavior; open field and light-dark tests assessed anxiety and exploration; the Morris water maze tested memory and spatial learning; rotarod assessed balance and motor coordination; and the novel object test assessed recognition memory.ResultsOur findings demonstrate that TPH2 KI mice exhibited increased depression-like behavior in the forced swim and tail suspension tests; increased avoidance in the light-dark and open field tests revealed anxiety-like phenotypes. Furthermore, serotonin deficit decreased locomotion and coordination in the rotarod. In the novel object, recognition memory was impaired, but spatial learning and memory in the Morris water were unaffected. Homozygotes displayed more severe phenotypes than heterozygotes, indicating a gene dosage-dependent effect.ConclusionsOur findings extend prior behavioral characterizations of TPH2 KI mice by providing an integrated profile at 6-month age point, revealing domain-specific effects across mood, anxiety, locomotion, and recognition memory.

To evaluate the outcomes of preimplantation genetic testing for structural rearrangements for individuals with pericentric or paracentric inversions undergoing in vitro fertilization. This retrospective study included trophectoderm (TE) embryo biopsy samples analyzed at a single reference laboratory from 37 reproductive couples who underwent 44 in vitro fertilization cycles. TE biopsies and parental samples were genotyped using Illumina CytoSNP-12b microarrays with bioinformatic analysis to determine the parental origin of each chromosome. For 137 TE biopsy samples with results from 24 individuals with pericentric inversions, the frequency of deletions and duplications related to the inversion was analyzed based on the relative size of the inverted segment. We observed a rate of 5% inversion-associated deletions and duplications for samples from individuals with inversions <30% of the chromosome, 3% from inversions 30% to 50% of the chromosome, and 21% from inversions >50% of the chromosome. Of 43 TE biopsy samples from 7 individuals with paracentric inversions, 2% had inversion-associated deletions and duplications, and 7% had monosomy related to the parental inversion, all of which were from 1 individual. Although previously considered to have minimal reproductive impact, we identified inversion-associated abnormalities in TE biopsy samples from individuals with paracentric and small pericentric inversions, underscoring a small but meaningful reproductive risk associated with these rearrangements.

The American College of Medical Genetics and Genomics Medical Directors' Special Interest Group (SIG) began in 2021 as a forum for directors of medical genetics clinical groups to share questions, concerns, current practices, and solutions regarding clinical operations. We report on the first 4 years of the SIG-its membership growth and SIG activities. We also present quantitative and qualitative results of a nationwide survey of 66 SIG members addressing recurrent questions from members regarding: wait times, volume of referrals, clinical workload expectations, and independent practice of genetic counselors (GCs) and advanced practice providers. Cross-sectional survey of American College of Medical Genetics and Genomics Medical Directors' Special Interest Group members. We found that clinical full-time equivalents expectations are higher for medical geneticists than advanced practice providers, which were higher than for GCs. In 76% (44/58) of programs, GCs see patients independently, although many require a medical geneticist cosignature for orders, and only 51% (30/59) of programs report that GCs can bill independently. Clinic wait times for routine visits vary by subspecialty; the longest wait times are for general pediatric and adult genetic services (49% [21/43] of visits had wait times > 6 months), whereas wait times > 6 months were reported for only 26% (9/34) of cancer genetic visits, 7% (3/43) of biochemical genetics visits, and 0% (0/26) of prenatal visits. Urgent visit wait times were generally less than 2 weeks. Wait times for clinical genetics appointments continue to increase compared with surveys from previous years. Medical genetics clinics are comprised of a heterogeneous workforce, and strategies to reduce wait times are similarly diverse.

Efforts to increase diversity, equity, and inclusion (DEI) in academia have created additional opportunities and burdens for individuals from underrepresented groups. The "minority tax" or "cultural taxation" is defined as additional or extra responsibilities distinctly placed on minoritized faculty in the name of DEI efforts. The "minority tax" is something all too familiar to individuals from marginalized groups; however, this concept has not been addressed broadly in the context of the medical and human genetics workforce. In the 2023 American College of Medical Genetics and Genomics annual conference, the authors were given the opportunity to organize a plenary session solely dedicated to DEI with a focus on how to address the "minority tax" and turn it into "minority capital." Approximately 400 individuals participated in the live Q&A and polling, and almost 700 participants evaluated the session afterward. Although the concept of the minority tax was entirely new to some, for many others, this topic resonated deeply as part of their lived experiences. Quotes by participants showed the session's influence on self-reflection, self-advocacy, and peer advocacy. Additional individual and institutional structured efforts are needed to help minoritized individuals gain awareness and knowledge to transform minority taxation to capital.

Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and variant interpretation burden. To address these limitations, a comprehensive clinical genome CVD test with semiautomated interpretation was developed. Monogenic conditions and risk alleles were selected based on the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary findings genes, pharmacogenomic (PGx) variants, and CVD-associated polygenic risk scores (PRS) were also assessed for inclusion. Test performance was modeled using 2594 genomes from the 1000 Genomes Project and further investigated in 20 previously tested individuals. The CVD genome test comprises a panel of 215 high-confidence CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes, and a PRS for coronary artery disease. Modeling of test performance using samples from the 1000 Genomes Project revealed approximately 6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, 1% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9 to 96 minutes. A genome-sequencing-based CVD genetic risk assessment test can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semiautomated and limited interpretation burden suggest that this testing approach can be scaled to support population-level initiatives in phenotypically enriched populations.