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Health Professionals\u27 Preferences for Next-Generation Sequencing in the Diagnosis of Suspected Genetic Disorders in the Paediatric Population.
Get PDFBackground/Objectives: Next-generation sequencing (NGS) can explain how genetics influence morbidity and mortality in children. However, it is unclear whether health providers will perceive and use such treatments. We conducted a discrete choice experiment (DCE) to understand Italian health professionals’ preferences for NGS to improve the diagnosis of paediatric genetic diseases. Methods: The DCE was adminis- tered online to 125 health professionals in Italy. We documented attributes influencing professionals’ decisions of NGS, including higher diagnostic yield, shorter counselling periods, cost, turnaround time, and the identification of fewer variants of unknown sig- nificance. Results: Results show that factors such as higher diagnostic yield, shorter counselling periods, lower costs, and faster turnaround times positively influenced the adoption of NGS tests. Willingness to pay (WTP) estimates varied from EUR 387 (95% CI, 271.8–502.9) for 7% increase in the diagnostic yield to EUR 469 (95% CI, 287.2–744.9) for a decrease of one week in the turnaround time. Responders would reduce diagnostic yield by 7% to decrease the turnaround time by one week in both the preference and the willingness to trade (WTT) spaces. Respondents prioritised diagnostic yield (RI = 50.36%; 95% CI 40.2–67.2%) compared to other attributes. Conclusions: therefore, health profes- sionals value NGS for allowing earlier, more accurate genetic diagnoses
Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.
Get PDFMutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD–associated mutation in TDP-43 (TardbpG348C) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43–deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD
Workshop Report-Heterogeneity and Successful Aging Part II: Approaches to Investigate Heterogeneity in Aging Research.
No full textHeterogeneity in aging is a fundamental biological process arising from multifactorial etiologies, including genetic, lifestyle, and socioeconomic factors. Modeling this heterogeneity in animal systems is critical for elucidating the underlying mechanisms of aging and for leveraging these insights in translational research. Here we present part II, a summary of the model organism research presented at the NIA Heterogeneity and Successful Aging workshop, held in May 2023
Absence of Glaucoma in Tg-MYOCY437H Mice of Diverse Genetic Backgrounds.
No full textPURPOSE: Mutations in the myocilin (MYOC) gene cause elevated intraocular pressure and glaucoma. To better understand the factors influencing susceptibility to glaucoma, we studied the MYOC mutation (MYOCY437H).
METHODS: We characterized ocular phenotypes in Tg-MYOCY437H mice on nine different mouse strain backgrounds.
RESULTS: No glaucoma-related phenotypes were observed. We detected neither elevated intraocular pressure (daytime readings) nor optic nerve degeneration differences between wild type (WT) and Tg-MYOCY437H mice. This included an absence of Tg-MYOCY437H-induced phenotypes on a mixed B6SJL background that best reflected the original publications with this strain. We confirmed that this result was not due to an absence of transgene expression in ocular tissues.
CONCLUSIONS: Our data indicate undefined complexity and that the previously reported glaucoma phenotypes are not robust across all institutions and environments
The HUGO Clinical Genomics & Genomic Medicine Education Survey: clinicians globally need and want genomic medicine training.
No full textBACKGROUND: The Clinical Genomics & Genomic Medicine Education subcommittee of the Human Genome Organization (HUGO) reports on the results of an exploratory genomic medicine survey of healthcare providers (clinicians) in low- and middle-income countries.
RESULTS: 281 clinicians from 17 low- and middle-income countries responded to the survey. Representing 20 medical specialties, only 13.6% of clinician respondents are comfortable when discussing genomics in clinical settings. Over 90% of clinicians recognize that genetics and genomics are relevant to their practice and that there needs to be genetics/genomic assessment of patients. Respondents report a wide range of learning style preferences including self-paced online (asynchronous) and live-online educational programming covering introductory content, clinical guidelines for monogenic disorders and when to utilize genetic or genomic testing.
CONCLUSIONS: Clinician respondents recognize the importance of genomics and are eager for continuing medical education. Reponses from the survey suggest that a larger scale, second phase survey should be distributed globally.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-025-00841-7
Under the lens: Taking a close look at the NIH and FDA declarations on animal-based research.
No full textGeneration and characterization of a knockout mouse of an enhancer of EBF3.
No full textGenomic studies of neurodevelopmental disorders (NDDs) have identified several relevant genomic variants. EBF3 is a gene with an excess of protein-coding de novo variants and underlies Hypotonia, Ataxia, and Delayed Development Syndrome. We previously identified noncoding de novo variants in an enhancer of EBF3 and further found enrichment of deletions of this enhancer in NDDs. In this study, we generated a novel mouse line that deletes the highly conserved, orthologous mouse region within the Rr169617 regulatory region, and characterized the molecular and phenotypic aspects of this mouse model. We found a deviation from Mendelian expectation (P=0.02) with significant depletion of the deletion allele (P=5.8×10-4). Rr169617+/- mice had a reduction of Ebf3 expression by 10% and Rr169617-/- mice had a reduction by 20%. Differential expression analyses in E12.5 forebrain, midbrain, and hindbrain in Rr169617+/+ versus Rr169617-/- mice identified dysregulated genes including histone and brain development related genes. A priori phenotyping analysis (open field, hole board and light/dark transition) identified sex-specific differences in mobility only for Rr169617-/- mice across multiple behavioral assays with Rr169617-/- males less mobile than Rr169617-/- females. Furthermore, both sexes when homozygous for the enhancer deletion displayed body composition differences when compared to wildtype mice. Overall, we show that deletion within Rr169617 reduces expression of Ebf3 and results in phenotypic outcomes consistent with potential sex specific behavioral differences
RNA binding of GAPDH controls transcript stability and protein translation in acute myeloid leukemia.
No full textDysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukaemia (AML) RBPs are key regulators of tumour proliferation. While classical RBPs have defined RNA binding domains, RNA recognition and function in AML by non-canonical RBPs (ncRBPs) remain unclear. Given the inherent complexity of targeting AML broadly, our goal was to uncover potential ncRBP candidates critical for AML survival using a CRISPR/Cas-based screening. We identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a pro-proliferative factor in AML cells. Based on cross-linking and immunoprecipitation (CLIP), we are defining the global targetome, detecting novel RNA targets mainly located within 5\u27UTRs, including GAPDH, RPL13a, and PKM. The knockdown of GAPDH unveiled genetic pathways related to ribosome biogenesis, translation initiation, and regulation. Moreover, we demonstrated a stabilizing effect through GAPDH binding to target transcripts including its own mRNA. The present findings provide new insights on the RNA functions and characteristics of GAPDH in AML
Automating candidate gene prioritization with large language models: from naive scoring to literature-grounded validation.
No full textMOTIVATION: Identifying promising therapeutic targets from thousands of genes in transcriptomic studies remains a major bottleneck in biomedical research. While large language models (LLMs) show potential for gene prioritization, they suffer from hallucination and lack systematic validation against expert knowledge.
RESULTS: The framework identified 609 sepsis-relevant genes with \u3e94% filtering efficiency, demonstrating strong enrichment for inflammatory pathways including TNF-α signaling, complement activation, and interferon responses. Literature validation yielded 30 ultra-high confidence therapeutic candidates, including both established sepsis genes (IL10, TREM1, S100A9, NLRP3) and novel targets warranting investigation. Benchmark validation against expert-curated databases achieved 71.2% recall, with systematic correlation between computational confidence and evidence quality. The final candidate set balanced discovery (11 novel genes) with validation (19 known genes), maintaining biological coherence throughout the filtering process. This framework demonstrates that rigorous methodology can transform unreliable LLM outputs into systematically validated biological insights. By combining computational efficiency with literature grounding, the approach provides a practical tool for prioritizing experimental validation efforts. The modular design enables adaptation to other diseases through knowledge base substitution, offering a systematic approach to literature-guided biomarker discovery.
AVAILABILITY AND IMPLEMENTATION: We developed a two-stage computational framework that combines LLM-based screening with literature validation for systematic gene prioritization. Starting with 10 824 genes from the BloodGen3 repertoire, we applied multi-criteria evaluation for sepsis relevance, followed by retrieval-augmented generation using 6346 curated sepsis publications. A novel faithfulness evaluation system verified that LLM predictions aligned with retrieved literature evidence. Source code and implementation details are available at https://github.com/taushifkhan/llm-geneprioritization-framework, vector database at https://doi.org/10.5281/zenodo.15802241, and Interactive demonstration at https://llm-geneprioritization.streamlit.app/
Expanding and refining the Mammalian Phenotype Ontology to enhance disease model discovery.
No full textThe mouse is a premier model system for investigating gene function and modeling human disease. For almost 40 years, Mouse Genome Informatics has worked to capture and integrate the data generated from mouse studies. A critical component of this integration is the development and use of the Mammalian Phenotype (MP) Ontology to capture the morphological and physiological effects of alterations to gene function in the mouse. As the wealth of phenotype data captured using the MP has expanded, its utility in the diagnosis of human disease has increased. Tools have been developed to use mouse and human phenotypes in variant identification. To enhance the applicability of the MP in disease diagnosis and increase the ability of researchers to find models for specific research questions, we have undertaken a disease-focused expansion of the MP. In addition, we have worked to improve the alignment of the MP to the Human Phenotype Ontology to make automated translation between mouse and human phenotypes easier and more reliable