Genome Medicine最新文献

{"title":"The dynamics of the gut microbiota in prediabetes during a four-year follow-up among European patients-an IMI-DIRECT prospective study.","authors":"Liwei Lyu, Yong Fan, Josef Korbinian Vogt, Marc Clos-Garcia, Amelie Bonnefond, Helle Krogh Pedersen, Avirup Dutta, Robert Koivula, Sapna Sharma, Kristine Højgaard Allin, Caroline Brorsson, Henna Cederberg, Elizaveta Chabanova, Federico De Masi, Emmanouil Dermitzakis, Petra J Elders, Marieke T Blom, Monika Hollander, Rebeca Eriksen, Ian Forgie, Gary Frost, Giuseppe N Giordano, Harald Grallert, Mark Haid, Tue Haldor Hansen, Bernd Jablonka, Tarja Kokkola, Anubha Mahajan, Andrea Mari, Timothy J McDonald, Petra B Musholt, Imre Pavo, Cornelia Prehn, Martin Ridderstråle, Hartmut Ruetten, Leen M 't Hart, Jochen M Schwenk, Evelina Stankevic, Henrik S Thomsen, Jagadish Vangipurapu, Henrik Vestergaard, Ana Viñuela, Mark Walker, Torben Hansen, Allan Linneberg, Henrik Bjørn Nielsen, Søren Brunak, Mark I McCarthy, Philippe Froguel, Jerzy Adamski, Paul W Franks, Marku Laakso, Joline W J Beulens, Ewan Pearson, Oluf Pedersen","doi":"10.1186/s13073-025-01508-7","DOIUrl":"10.1186/s13073-025-01508-7","url":null,"abstract":"<p><strong>Background: </strong>Previous case-control studies have reported aberrations of the gut microbiota in individuals with prediabetes. The primary objective of the present study was to explore the dynamics of the gut microbiota of individuals with prediabetes over 4 years with a secondary aim of relating microbiota dynamics to temporal changes of metabolic phenotypes.</p><p><strong>Methods: </strong>The study included 486 European patients with prediabetes. Gut microbiota profiling was conducted using shotgun metagenomic sequencing and the same bioinformatics pipelines at study baseline and after 4 years. The same phenotyping protocols and core laboratory analyses were applied at the two timepoints. Phenotyping included anthropometrics and measurement of fasting plasma glucose and insulin levels, mean plasma glucose and insulin under an oral glucose tolerance test (OGTT), 2-h plasma glucose after an OGTT, oral glucose insulin sensitivity index, Matsuda insulin sensitivity index, body mass index, waist circumference, and systolic and diastolic blood pressure. Measures of the dynamics of bacterial microbiota were related to concomitant changes in markers of host metabolism.</p><p><strong>Results: </strong>Over 4 years, significant declines in richness were observed in gut bacterial and viral species and microbial pathways accompanied by significant changes in the relative abundance and the genetic composition of multiple bacterial species. Additionally, bacterial-viral interactions diminished over time. Despite the overall reduction in bacterial richness and microbial pathway richness, 80 dominant core bacterial species and 78 core microbial pathways were identified at both timepoints in 99% of the individuals, representing a resilient component of the gut microbiota. Over the same period, individuals with prediabetes exhibited a significant increase in glycemia and insulinemia alongside a significant decline in insulin sensitivity. Estimates of the gut bacterial microbiota dynamics were significantly correlated with temporal impairments in host metabolic health.</p><p><strong>Conclusions: </strong>In this 4-year prospective study of European patients with prediabetes, the gut microbiota exhibited major changes in taxonomic composition, bacterial species genetics, and microbial functional potentials, many of which paralleled an aggravation of host metabolism. Whether the temporal gut microbiota changes represent an adaptation to the progression of metabolic abnormalities or actively contribute to these in prediabetes cases remains unsettled.</p><p><strong>Trial registration: </strong>The Diabetes Research on Patient Stratification (DIRECT) study, an exploratory observational study initiated on October 15, 2012, was registered on ClinicalTrials.gov under the number NCT03814915.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"78"},"PeriodicalIF":10.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups.","authors":"Enze Liu, Oumaima Jaouadi, Riya Sharma, Nathan Becker, Travis S Johnson, Parvathi Sudha, Vivek S Chopra, Faiza Zafar, Habib Hamidi, Charlotte Pawlyn, Attaya Suvannasankha, Rafat Abonour, Brian A Walker","doi":"10.1186/s13073-025-01503-y","DOIUrl":"10.1186/s13073-025-01503-y","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy is now standard of care for multiple myeloma (MM), where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D (GPRC5D). However, additional novel targets are needed to counter tumor heterogeneity, therefore new strategies to identify additional targets are also required.</p><p><strong>Methods: </strong>We utilized multi-omics data from two large datasets A framework that utilized prior knowledge of cell surface potential, expression in healthy organs, and expression level in MM cells was established to define novel immunotherapeutic targets. High confidence targets were prioritized for myeloma populations and subgroups, validated with flow cytometry and immunoblotting.</p><p><strong>Results: </strong>Novel population-level candidate targets such as ITGA4 and LAX1, as well as subtype-specific targets including ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), CD180 in hyperdiploidy, GPRC5D in 1q gain, and ADAM28 in biallelic TP53 samples were identified. Candidate target surface expression was validated by flow cytometry and CRISPR-Cas9 knock-out models. Sub-clonal differences in expression were noted, using single-cell RNA-seq data. Additionally, alternative splicing of existing immunotherapy targets, such as FCRL5, was noted as a potential mechanism of antigen loss.</p><p><strong>Conclusions: </strong>Our study presents a methodology to identify novel candidate immunotherapy targets. We also use known genomic data to identify subtype-specific targets that could be used either as complementary or alternative targets to existing treatments. We show that immunotherapy targets can have heterogenous expression within a patient, which can affect treatment efficacy. Taken together, our study establishes a robust methodology to identify novel therapeutic targets in MM, revealing critical insights that will inform the development of current and next-generation immunotherapies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"79"},"PeriodicalIF":10.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PGSFusion streamlines polygenic score construction and epidemiological applications in biobank-scale cohorts.","authors":"Sheng Yang, Xiangyu Ye, Xiaolong Ji, Zhenghui Li, Min Tian, Peng Huang, Chen Cao","doi":"10.1186/s13073-025-01505-w","DOIUrl":"10.1186/s13073-025-01505-w","url":null,"abstract":"<p><strong>Background: </strong>The polygenic score (PGS) is an estimate of an individual's genetic susceptibility to a specific complex trait and has been instrumental to the development of precision medicine. As an increasing number of genome-wide association studies (GWAS) have emerged, numerous sophisticated statistical and computational methods have been developed to facilitate the PGS construction. However, both the complex statistical estimation procedure and the various data formats of summary statistics and reference panel make the PGS calculation challenging and not easily accessible to researchers with limited statistical and computational backgrounds.</p><p><strong>Results: </strong>Here, we propose PGSFusion, a webserver designed to carry out PGS construction for targeting variety of analytic requirements while requiring minimal prior computational knowledge. Implemented with well-established web development technologies, PGSFusion streamlines the construction of PGS using 17 PGS methods in four categories: 11 single-trait, one multiple-trait, two annotation-based and three cross-ancestry based methods. In addition, PGSFusion also utilizes UK Biobank data to provide two kinds of in-depth analyses for 201 complex traits: i) prediction performance evaluation to display the consistency between PGS and specific traits and the effect size of PGS in different genetic risk groups; ii) joint effect analysis to investigate the interaction between PGS and covariates, as well as the effect size of covariates in different genetic subgroups. PGSFusion benchmarks the prediction performances for different methods in one summary statistics. PGSFusion automatically identifies the required parameters in different data formats of uploaded GWAS summary statistics files, provides a selection of suitable methods, and outputs calculated PGSs and their corresponding epidemiological results. Finally, we showcase three case studies in different application scenarios, highlighting its versatility and values to researchers.</p><p><strong>Conclusions: </strong>Overall, PGSFusion presents an easy-to-use, effective, and extensible platform for PGS construction, promoting the accessibility and utility of PGS for researchers in the field of precision medicine. PGSFusion is freely available at http://www.pgsfusion.net/ .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"77"},"PeriodicalIF":10.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Joint inference of mutational signatures from indels and single-nucleotide substitutions reveals prognostic impact of DNA repair deficiencies.","authors":"Patricia Ferrer-Torres, Iván Galván-Femenía, Fran Supek","doi":"10.1186/s13073-025-01497-7","DOIUrl":"10.1186/s13073-025-01497-7","url":null,"abstract":"<p><strong>Background: </strong>Mutational signatures are increasingly used to understand the mechanisms causing cancer. However, their important applications in predicting prognosis and stratifying patients for therapy are hampered by inaccurate inference of the various featureless, dense trinucleotide mutational spectra, which are often confounded with one another. One of them is the homologous recombination deficiency (HRd)-associated signature SBS3, relevant because of its association with prognosis in ovarian and breast cancer and because of its potential as a biomarker for synthetic lethality therapies.</p><p><strong>Methods: </strong>Here, we highlight strong benefits of a multimodal approach for mutational signature extraction, applied on top of standard bioinformatic pipelines. By jointly operating on single-base substitution (SBS) and indel (ID) spectra, this method enables accurate identification of various DNA repair deficiency signatures and patient survival prediction.</p><p><strong>Results: </strong>Across four different cohorts of whole-genome sequenced high-grade serous ovarian cancers (HGSOC), the multimodal SBS + ID approach correctly distinguished the commonly confused signatures SBS3, SBS5, SBS8, SBS39, and SBS40. Importantly, we robustly identified two different multimodal SBS3 signatures, m-SBS3a and m-SBS3b, with distinct patterns in the indel spectrum. Multimodal SBS3b signature was strongly predictive of longer survival in ovarian cancer patients, replicating across four cohorts, with effect sizes greatly exceeding other genetic markers. Our m-SBS3 also predicted survival in platinum-treated patients with various cancer types, and moreover, the SBS + ID joint inference was successfully applied to mismatch repair-deficient colorectal cancer and immunotherapy response, supporting a general utility of the multimodal mutational signatures approach.</p><p><strong>Conclusions: </strong>Overall, combining SBS and ID mutations improves detection of HR deficiency-associated signatures and reveals distinct SBS3 subtypes with prognostic value. This multimodal approach outperforms existing markers and is readily applicable to therapy stratification.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"76"},"PeriodicalIF":10.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort.","authors":"Jamie C Stark, Neta Pipko, Yijing Liang, Anna Szuto, Chung Ting Tsoi, Megan A Dickson, Kyoko E Yuki, Huayun Hou, Sydney Scholten, Kenzie Pulsifer, Meryl Acker, Meredith Laver, Harsha Murthy, Olivia M Moran, Emily Bonnell, Nicole Liang, Jashanpreet Sidhu, Lucie Dupuis, Mohammad M Ghahramani Seno, Marisa Chard, Rebekah K Jobling, Jessie Cameron, Rose Chami, Michal Inbar-Feigenberg, Michael D Wilson, David A Chitayat, Kym M Boycott, Lianna Kyriakopoulou, Roberto Mendoza-Londono, Christian R Marshall, James J Dowling, Gregory Costain, Ashish R Deshwar","doi":"10.1186/s13073-025-01494-w","DOIUrl":"10.1186/s13073-025-01494-w","url":null,"abstract":"<p><strong>Background: </strong>RNA sequencing (RNA-seq) is emerging as a valuable tool for identifying disease-causing RNA transcript aberrations that cannot be identified by DNA-based testing alone. Previous studies demonstrated some success in utilizing RNA-seq as a first-line test for rare inborn genetic conditions. However, DNA-based testing (increasingly, whole genome sequencing) remains the standard initial testing approach in clinical practice. The indications for RNA-seq after a patient has undergone DNA-based sequencing remain poorly defined, which hinders broad implementation and funding/reimbursement.</p><p><strong>Methods: </strong>In this study, we identified four specific and familiar clinical scenarios, and investigated in each the diagnostic utility of RNA-seq on clinically accessible tissues: (i) clarifying the impact of putative intronic or exonic splice variants (outside of the canonical splice sites), (ii) evaluating canonical splice site variants in patients with atypical phenotypes, (iii) defining the impact of an intragenic copy number variation on gene expression, and (iv) assessing variants within regulatory elements and genic untranslated regions.</p><p><strong>Results: </strong>These hypothesis-driven RNA-seq analyses confirmed a molecular diagnosis and pathomechanism for 45% of participants with a candidate variant, provided supportive evidence for a DNA finding for another 21%, and allowed us to exclude a candidate DNA variant for an additional 24%. We generated evidence that supports two novel Mendelian gene-disease associations (caused by variants in PPP1R2 and MED14) and several new disease mechanisms, including the following: (1) a splice isoform switch due to a non-coding variant in NFU1, (2) complete allele skew from a transcriptional start site variant in IDUA, and (3) evidence of a germline gene fusion of MAMLD1-BEND2. In contrast, RNA-seq in individuals with suspected rare inborn genetic conditions and negative whole genome sequencing yielded only a single new potential diagnostic finding.</p><p><strong>Conclusions: </strong>In summary, RNA-seq had high diagnostic utility as an ancillary test across specific real-world clinical scenarios. The findings also underscore the ability of RNA-seq to reveal novel disease mechanisms relevant to diagnostics and treatment.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"72"},"PeriodicalIF":10.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiome-based therapeutics towards healthier aging and longevity.","authors":"Saurabh Kadyan, Gwoncheol Park, Tejinder P Singh, Cole Patoine, Saiful Singar, Teresa Heise, Christin Domeier, Chester Ray, Manoj Kumar, Pradip V Behare, Paramita Chakrabarty, Philip Efron, Julia Sheffler, Ravinder Nagpal","doi":"10.1186/s13073-025-01493-x","DOIUrl":"10.1186/s13073-025-01493-x","url":null,"abstract":"<p><p>The gut microbiome is our lifetime companion, regulating our health from birth throughout the lifespan. The gut microbiome composition changes continually with age, influencing both physiological and immunological development. Emerging evidence highlights the close association, and thus implication, of the microbiome with healthy disease-free aging and longevity. Accordingly, targeting the gut microbiome is emerging as a promising avenue to prevent, alleviate, and ameliorate aging-related disorders. Herein, we provide a prospective and inclusive framework of the close connection of the gut microbiome with human aging, while contemplating how this association is intertwined with age-related diseases. We delve into recently emerging and potential microbiome-based therapeutics that are projected to aid in alleviating myriad aging-related diseases, thereby enhancing the health and well-being of the aging population. Finally, we present a foundation and perspective underlining the prospects of microbiome-based therapeutics developed and tailored precisely for the elderly, with the overarching goal of promoting health and longevity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"75"},"PeriodicalIF":10.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High genetic relatedness between multidrug resistant bacteria before and after the 2022 invasion of Ukraine.","authors":"Francois Lebreton, Viacheslav Kondratiuk, Valentyn Kovalchuk, Niels Pfennigwerth, Ting L Luo, Brendan T Jones, Nadiia Fomina, Frieder Fuchs, Jörg B Hans, Jessica Eisfeld, Ana Ong, Sören Gatermann, Jason W Bennett, Patrick Mc Gann","doi":"10.1186/s13073-025-01500-1","DOIUrl":"10.1186/s13073-025-01500-1","url":null,"abstract":"<p><strong>Background: </strong>The Russian invasion of Ukraine in 2022 has placed extraordinary pressure on hospitals there. One consequence of this has been the alarming increase in infections caused by multi-drug resistant organisms (MDROs), both within Ukraine and among the Ukrainian diaspora. The original source of these MDROs remains obscure although nosocomial origin is suspected. Here, we analyzed a collection of Acinetobacter baumannii and Pseudomonas aeruginosa collected from Ukraine before and after the invasion to glean a greater understanding of their relationship and origins.</p><p><strong>Methods: </strong>Genomic analysis was conducted on 167 A. baumannii and 93 P. aeruginosa cultured from 223 Ukrainian patients hospitalized in Ukraine or other European countries. Fifty-three isolates were cultured between 2014 and 2021, prior to the invasion, and the remaining 207 after.</p><p><strong>Results: </strong>Highly genetically related extensively-drug resistant (XDR) clones were identified that spanned the pre- and post-invasion periods. For A. baumannii, isolates encompassed three sequence types (STs), including carbapenemase-producing strains from ST-2 (bla_OXA-23) and ST-78 (bla_OXA-72), as well as ST-400 carrying the ESBL bla_GES-11. For P. aeruginosa, isolates encompassed three STs: ST-773 carrying bla_NDM-1, ST-1047 carrying bla_IMP-1, and ST-244. For all, the mobile genetic elements associated with carbapenemase carriage were fully characterized. Notably, post-invasion ST-773 and ST-1047 P. aeruginosa had a signature of host adaptation with multiple loss-of-function mutations in the quorum-sensing regulator LasR, known to modulate immune responses and provide survival advantages in animal models of infection.</p><p><strong>Conclusions: </strong>XDR epidemic clones circulating in Ukraine and across Europe since 2022 share a close genetic relationship to historical strains from Ukraine. In some cases, direct links to medical facilities within Ukraine can be inferred. These data suggest that surveillance efforts should focus on tracking nosocomial transmission within Ukrainian hospitals while infection control efforts are being disrupted by the ongoing Russian invasion.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"74"},"PeriodicalIF":10.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding how gene-disease relationships can impact clinical utility: adaptations and challenges in hereditary cancer testing.","authors":"Jennifer Herrera-Mullar, Carolyn Horton, Amybeth Weaver, Meghan Towne, Jennifer M Huang, Grace E VanNoy, Steven M Harrison, Bess Wayburn","doi":"10.1186/s13073-025-01499-5","DOIUrl":"10.1186/s13073-025-01499-5","url":null,"abstract":"<p><strong>Background: </strong>Defining gene-disease relationships (GDRs) influences the clinical utility of hereditary cancer predisposition (HCP) multigene panel testing (MGPT) results, as variant classification relies directly on gene-disease characterization. GDR characterization for HCP is challenging due to disease prevalence, incomplete penetrance, and heterogeneity. There is insufficient data showing how gene-disease validity (GDV) scores of HCP genes affect variant classification and how GDV scores change over time. Though these issues determine the results of HCP-MGPT, their impact on short- and long-term clinical utility has not been explored in-depth.</p><p><strong>Methods: </strong>Using an evidence-based GDV framework, genes were classified into five standardized GDV categories at the time of panel addition. We curated changes in GDV scores and classifications for HCP-MGPT over 7 years. The corresponding impact on the frequency of positive and variant of uncertain significance (VUS) results was evaluated by GDV score.</p><p><strong>Results: </strong>Positive results were most common in Definitive evidence genes (31.5%), with none in Limited evidence genes (0%). Genes with Definitive GDRs (n = 42) remained Definitive, while most genes with Strong (6/10, 60%) and Moderate (19/24, 80%) GDRs changed categories, 8 (23.5%) of which received a clinically significant GDR downgrade. GDRs associated with low-moderate risk of breast cancer were significantly more likely to be downgraded compared to GDRs associated with rarer, high-penetrance specific phenotypes (p < 0.0001). Downgrades for all GDRs were due to new published data and updates to the GDV framework (77%, 10/13), with 23% (3/13) due to framework updates alone. Including Limited evidence genes on MGPT increased the VUS frequency by 13.7% percentage points.</p><p><strong>Conclusions: </strong>Positive and VUS results varied by GDV category, and Limited evidence genes did not contribute to diagnostic yield. No Limited evidence genes in the category for ≥ 3 years (n = 8) were upgraded, indicating that including these genes on HCP-MGPT provides limited long-term clinical utility. Our data highlight that GDV assessment for HCP requires robust evidence and must account for variable disease penetrance and elevated prevalence in the population. Balancing the availability of a comprehensive gene menu and transparency surrounding clinical utility of novel genes will maximize identification of high-risk patients while reducing the risk of misdiagnosis through clinical false-positive results.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"73"},"PeriodicalIF":10.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.","authors":"I-Na Lu, Louisa Müller-Miny, Carolin Krekeler, Phyllis Fung-Yi Cheung, Georgia Antonopoulou, Astrid Jeibmann, Andreas Schulte-Mecklenbeck, Kornelius Kerl, Simon Call, Christian Reicherts, Annalen Bleckmann, Matthias Stelljes, Georg Lenz, Heinz Wiendl, Gerd Meyer Zu Hörste, Oliver M Grauer","doi":"10.1186/s13073-025-01498-6","DOIUrl":"10.1186/s13073-025-01498-6","url":null,"abstract":"<p><strong>Background: </strong>Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and potentially life-threatening complication of chimeric antigen receptor (CAR) T cell therapy. The underlying mechanisms of ICANS remain incompletely understood and are unlikely to be explained by cytokine excess alone.</p><p><strong>Methods: </strong>We analyzed paired peripheral blood and cerebrospinal fluid (CSF) samples from CAR T cell-treated patients who developed ICANS (n = 11) within 5-21 days post-infusion. ICANS severity was graded as follows: grade 1 (n = 3), grade 2 (n = 4), grade 3 (n = 1), and grade 4 (n = 3). Control samples were obtained from patients with idiopathic intracranial hypertension, functional neurological disorders, and multiple sclerosis. We employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to profile immune cell populations and performed multi-modal spatial transcriptomics and immunofluorescence on postmortem choroid plexus and brain tissue from a patient with fatal grade 4 ICANS.</p><p><strong>Results: </strong>We identified a distinct population of proliferating, cytotoxic T cells characterized by CXCR6 expression, enriched in CD4 + CAR T cells and predominantly localized in ICANS CSF. These CXCR6 + T cells were largely absent from control CSF samples. Spatial mapping of postmortem brain tissue revealed widespread infiltration of myeloid cells and a striking spatial association between CXCR6 + T cells and CXCL16-expressing myeloid cells in both the choroid plexus and brain parenchyma. Notably, CSF levels of CXCL16 positively correlated with ICANS severity across the cohort, from grade 1 to grade 4.</p><p><strong>Conclusions: </strong>Our findings implicate the CXCL16/CXCR6 axis in the recruitment of cytotoxic CAR CD4 + T cells to the central nervous system (CNS) during ICANS. This interaction may be linked to neuroinflammatory processes and severity stratification in ICANS pathogenesis. These results provide a mechanistic rationale for exploring CXCL16/CXCR6 as a potential biomarker and therapeutic target in CAR T cell-associated neurotoxicity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"71"},"PeriodicalIF":10.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma microRNA signatures of aging and their links to health outcomes and mortality: findings from a population-based cohort study.","authors":"Lieke M Kuiper, Michelle M J Mens, Julia W Wu, Jaap Goudsmit, Yuan Ma, Liming Liang, Albert Hofman, Trudy Voortman, M Arfan Ikram, Jeroen G J van Rooij, Joyce B J van Meurs, Mohsen Ghanbari","doi":"10.1186/s13073-025-01437-5","DOIUrl":"10.1186/s13073-025-01437-5","url":null,"abstract":"<p><strong>Background: </strong>MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and show differential expression in various tissues with aging phenotypes. Detectable in circulation, extracellular microRNAs reflect (patho)physiological processes and hold promise as biomarkers for healthy aging and age-related diseases. This study aimed to explore plasma extracellular microRNAs as a biological aging indicator and their associations with health outcomes using population-level data.</p><p><strong>Methods: </strong>We quantified plasma expression levels of 2083 extracellular microRNAs using targeted RNA-sequencing in 2684 participants from the population-based Rotterdam Study cohort. The training and test sets included 1930 participants from the advanced-aged initial and second subcohort (RS-I/RS-II; median age: 70.6), while the validation set comprised 754 participants from the middle-aged fourth subcohort (RS-IV; median age: 53.5). Based on 591 microRNAs well-expressed in plasma, we examined differential expression of microRNAs with chronological age, PhenoAge-a composite score of age and nine multi-system blood biomarkers-the frailty index, and mortality. Next, elastic net models were employed to construct composite microRNA-based aging biomarkers predicting chronological age (mirAge), PhenoAge (mirPA), frailty index (mirFI), and mortality (mirMort). The association of these aging biomarkers with different age-related health outcomes was assessed using Cox Proportional Hazard, linear regression, and logistic regression models in the test and validation sets.</p><p><strong>Results: </strong>We identified 188 microRNAs differentially expressed with chronological age within the RS-I/RS-II advanced-aged population (n_training = 1158, n_test = 772), of which 177 microRNAs (94.1%) were replicated in the middle-aged RS-IV subcohort (n_validation = 754). Moreover, 227 miRNAs showed robust associations with PhenoAge, 61 with FI, and 16 with 10-year mortality independent of chronological age. Subsequently, we constructed four plasma microRNA-based aging biomarkers: mirAge with 108, mirPA with 153, mirFI with 81, and mirMort with 50 miRNAs. Elevated scores on these microRNA-based aging biomarkers were associated with unfavorable health outcomes, including lower subjective physical functioning and self-reported health and increased mortality and frailty risk, but not with first- or multi-morbidity. Overall, larger effect estimates were observed for mirPA, mirFI, and mirMort compared to mirAge.</p><p><strong>Conclusions: </strong>This study describes distinct plasma microRNA-aging signatures and introduces four microRNA-based aging biomarkers with the potential to identify accelerated aging and age-related decline, providing insights into the intricate process of human aging.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"70"},"PeriodicalIF":10.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}