Genome Medicine最新文献

{"title":"Multi-omics profiles of sex hormone-binding globulin are associated with subclinical atherosclerosis in men with HIV.","authors":"Yi Wang, Xiaonan Xue, Mykhaylo Usyk, Anjali Sharma, Kathryn Anastos, Wendy S Post, Howard N Hodis, Zheng Wang, Mallory D Witt, Charles R Rinaldo, Todd T Brown, Frank J Palella, Stephen Gange, Mark H Kuniholm, Beverly E Sha, Patrick Caron, Robert E Gerszten, Clary B Clish, Chantal Guillemette, Robert D Burk, Robert C Kaplan, Qibin Qi, David B Hanna, Brandilyn A Peters","doi":"10.1186/s13073-026-01709-8","DOIUrl":"10.1186/s13073-026-01709-8","url":null,"abstract":"<p><strong>Background: </strong>Sex hormones and HIV infection both influence cardiovascular health. However, the association between sex hormones and subclinical atherosclerosis is not fully understood, especially in the context of HIV.</p><p><strong>Methods: </strong>Among 321 men (65% with HIV) from the MACS/WIHS Combined Cohort Study, we measured 14 serum sex hormones and sex hormone-binding globulin (SHBG), assessed carotid artery plaque (IMT > 1.5 mm) using high-resolution B-mode ultrasound, and performed metagenomic sequencing on stool samples. In 312 men, we measured 986 plasma metabolites via liquid chromatography-tandem mass spectrometry and 2883 plasma proteins using the Olink Explore 3072 platform. In stratified analyses of men with (MWH) and without HIV (MWOH) and adjusting for covariates and multiple testing, we (1) examined associations of sex hormones with plaque; (2) characterized multi-omics profiles related to sex hormones; and (3) generated sex hormone-related omics scores via linear combination of related species, metabolites, and proteins, respectively, to explore whether these sex hormone-related multi-omics profiles were associated with plaque.</p><p><strong>Results: </strong>Median age of participants was 62 years (interquartile range: 58-68), and 31.5% had carotid artery plaque. Sex hormones were differentially associated with plaque in MWH and MWOH. In MWH, an inverse association was observed between SHBG and plaque (OR = 0.60 per 1-SD increase, 95% CI: 0.41, 0.90). Furthermore, higher SHBG levels were associated with overall gut microbial composition, lower abundance of species from genera Prevotella, Fibrobacter and Coprococcus, higher levels of certain metabolites (primarily lipid and carnitine metabolites) and proteins enriched in the cell-cell adhesion pathway. Some SHBG-related species (e.g., Mediterranea massiliensis), metabolites (e.g., phosphatidylcholine-based lipids) and proteins (e.g., enriched in immune response pathway) were also associated with plaque in MWH. All three SHBG-related omics scores were inter-correlated and inversely associated with plaque in MWH. In MWOH, estrone-sulfate was positively associated with plaque (OR = 3.80, 95% CI: 1.41, 10.22) but not with any species, metabolites or proteins.</p><p><strong>Conclusions: </strong>Higher SHBG, and related microbial species, circulating metabolites, and proteins, were inversely associated with carotid artery plaque. These findings suggested that SHBG may play a protective role in subclinical atherosclerosis in MWH.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382051","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":"Multi-modal data integration reveals functionally credible predictive biomarkers in ovarian cancer.","authors":"Taru A Muranen, Andreas Hainari, Daria Afenteva, Wojciech Senkowski, Jaana Oikkonen, Johann Dreo, Kyriaki Driva, Susanna Holmström, Veli-Matti Isoviita, Alexandra Lahtinen, Kari Lavikka, Yilin Li, Marta Lovino, Ilari Maarala, Giovanni Marchi, Francesca Miccolis, Giulia Micoli, Matthieu Najm, Ann-Christin Ostwaldt, Pablo Rodriguez-Mier, Jenni Söderlund, Sakari Hietanen, Anni Virtanen, Julio Saez-Rodriguez, Elisa Ficarra, Benno Schwikowski, Erika Alanne, Krister Wennerberg, Sampsa Hautaniemi, Johanna Hynninen","doi":"10.1186/s13073-026-01706-x","DOIUrl":"10.1186/s13073-026-01706-x","url":null,"abstract":"<p><strong>Background: </strong>Precision oncology aims to tailor treatment according to tumor-specific molecular alterations, but the success of aberration-guided therapies has been limited in clinical trials. Here, we develop an integrated whole-genome and transcriptome workflow to systematically distinguish functionally credible, predictive driver aberrations from non-functional alterations across all classes of genomic events.</p><p><strong>Methods: </strong>We applied the integrated omics workflow to 335 patients with ovarian high-grade serous carcinoma (HGSC) enrolled in the observational DECIDER study. Tumor samples were collected from multiple cancer sites as part of the standard cancer care. DNA and RNA were extracted together from snap-frozen tumor samples and sent to whole-genome and transcriptome sequencing. Sequencing data were processed with the Anduril 2 pipeline for detection and validation of short somatic changes and with the HMW toolkit and the nf-core/rnafusion pipeline for assessment of structural changes. Aberration-specific drug sensitivity was tested in patient-derived organoids with a drug screen combining targeted agents and chemotherapy.</p><p><strong>Results: </strong>Using an agnostic integrated omics analysis, we identified clinically relevant ESCAT Tier II-III alterations in more than 40% of the patients, even though 58% of all nominally pathogenic variants proved to be false positives. Credible aberrations were predominantly clonal, detected across anatomical sites, and preserved from diagnosis to relapse, indicating early establishment during tumor evolution. The most recurrent actionable event was NF1 deficiency, which was associated with a robust transcriptional footprint and marked sensitivity to KRAS- and MEK-inhibition in patient-derived organoids. Notably, integrated DNA-RNA analysis enabled discrimination of treatment-guiding aberrations from false-positive findings that would otherwise misinform treatment selection and confound clinical trial outcomes.</p><p><strong>Conclusions: </strong>Our findings provide a strategy for more reliable biomarker detection in precision oncology, inform biomarker-guided clinical trial design, and reveal unexploited therapeutic vulnerabilities in HGSC.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381992","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":"Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK.","authors":"Michael Korenjak, Nuri Alpay Temiz, Stéphane Keita, Bérénice Chavanel, Claire Renard, Cécilia Sirand, Vincent Cahais, Tanguy Mayel, Karin R Vevang, Foster C Jacobs, Jiehong Guo, William E Smith, Marissa K Oram, Flaviu A Tăbăran, Ozan Ahlat, Ingrid Cornax, M Gerard O'Sullivan, Samrat Das, Shuvro P Nandi, Yuhe Cheng, Ludmil B Alexandrov, Silvia Balbo, Stephen S Hecht, Sergey Senkin, François Virard, Lisa A Peterson, Jiri Zavadil","doi":"10.1186/s13073-026-01685-z","DOIUrl":"10.1186/s13073-026-01685-z","url":null,"abstract":"<p><strong>Background: </strong>Tobacco use is linked to multiple cancer types and a quarter of cancer deaths. Tobacco smoke contains numerous mutagenic chemicals such as polycyclic aromatic hydrocarbons (PAH), however, the mutagenicity of many chemicals in tobacco products remains underexplored. The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), both International Agency for Research on Cancer (IARC) Group 1 carcinogens, form pre-mutagenic pyridyloxobutyl (POB) DNA adducts, yet little is known about the associated genomic mutation landscape(s) in humans.</p><p><strong>Methods: </strong>We applied bulk and error-corrected next-generation sequencing to a battery of experimental systems comprising mammalian cell lines and animals exposed to NNK or NNN, and the extracted mutational signatures were compared to POB DNA adducts formed in the same models. A genome-scale POB mutational signature was extracted and characterized in detail and subsequently used for optimized per-sample signature attribution in ~ 6,670 cancer genomes from the International Cancer Genome Consortium Pan-Cancer Analysis of Whole Genomes (ICGC PCAWG) and The Cancer Genome Atlas (TCGA) collections.</p><p><strong>Results: </strong>POB signatures generated in experimental exposure models share profiles dominated by T > N and C > T alterations, with transcription strand asymmetry indicative of damage on thymidines and cytidines. The T > N-dominated mutation profiles can be explained by O²-POB-dT adducts, detected in the exposed cells. Stringent screening of 6,668 cancer genomes revealed the presence of a genome-scale POB signature in ~ 350 tumors from sites associated with tobacco smoking, that were distinct from cancer sites typically linked to known smoking-related single base substitution (SBS) signatures SBS4 and SBS92 linked to PAHs. These included hematological malignancies and cancers of the kidney, prostate, pancreas and breast, among other sites. In contrast and as expected, tobacco-smoking signatures SBS4 and SBS92 were jointly or individually predominant in cancers of the lung, liver, head-and-neck or bladder.</p><p><strong>Conclusions: </strong>Our study provides first-of-its-kind evidence for the presence of a tobacco-specific nitrosamine mutational signature in human tumors. It suggests that the POB pathway may contribute selectively to the mutational landscapes of certain cancers distinct from those affected by PAH compounds, indicating the potential roles of specific tobacco smoke chemicals in tobacco-linked cancer types lacking SBS4 or SBS92.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and functional characterization of regulatory variants in DPP9 associated with COVID-19 severity.","authors":"Gaëlle Farah, Magali Torres, Leo Henches, Hugues Aschard, Jade Ghosn, Xavier Duval, Pascal Rihet, Salvatore Spicuglia, Sandrine Marquet","doi":"10.1186/s13073-026-01703-0","DOIUrl":"10.1186/s13073-026-01703-0","url":null,"abstract":"<p><strong>Background: </strong>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to a wide-range of clinical outcomes, which have been extensively studied through genome-wide association studies (GWAS).</p><p><strong>Methods: </strong>Starting from lead genetic variants associated with COVID-19 infection and severity, we identified a subset of non-coding candidate variants with potential regulatory functions. We combined bioinformatics analysis and functional screening in three cell lines to provide evidence for regulatory activity. We then performed a genetic study to test the association of our selected candidates with disease susceptibility followed by the functional validation of the risk haplotype.</p><p><strong>Results: </strong>We prioritized two DPP9 variants within a haplotype that increases the risk of severe COVID-19. This haplotype exhibited increased regulatory activity and altered transcription factor binding, suggesting its role in influencing COVID-19 severity by modulating DPP9 expression in immune and lung cell types.</p><p><strong>Conclusions: </strong>The interest of our study lies in the functional characterization of regulatory variants responsible for increased levels of DPP9 and lung damage observed in patients with severe COVID-19. These findings advance our understanding of genetic risk factors for COVID-19 and highlight functional SNPs that may guide future therapeutic research.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375530","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":"De novo variants in NPTN cause a neurodevelopmental disorder with autism and neuroplastin-PMCA hypofunction.","authors":"Yi Liang, Rodrigo Ormazabal-Toledo, Harini Srinivasan, Ayse Malci, Waldo Acevedo, Ulrich Thomas, Julie S Cohen, Nils Rahner, Johannes Luppe, Gabriella Vera, Francois Lecoquierre, Eden Kroin, Brad Angle, Hong Cui, Maria J Guillen Sacoto, Bert B A de Vries, Rolph Pfundt, Gillian Prinzing, Kimberly Wiltrout, Yakira Begun, Elaine M Pereira, Alexandra Afenjar, Caroline Nava, Konrad Platzer, Dirk Montag, Rodrigo Herrera-Molina","doi":"10.1186/s13073-026-01699-7","DOIUrl":"10.1186/s13073-026-01699-7","url":null,"abstract":"<p><strong>Background: </strong>NPTN encodes human neuroplastin (hNp), a transmembrane immunoglobulin (Ig)-superfamily glycoprotein and a subunit of the plasma membrane calcium (Ca²⁺)-ATPases (PMCA). The critical importance of hNp and its associations with PMCA in the human brain remains unknown.</p><p><strong>Methods: </strong>Here, we describe de novo NPTN variants in individuals with autism and mild-to-severe DD/ID and evaluate their effects using animal models and in silico, molecular, and cellular approaches.</p><p><strong>Results: </strong>Four individuals present variants affecting the two hNp isoforms, hNp55 and hNp65. Other four variants affect only the hNp65 isoform. Two individuals independently carry the same loss-of-function nonsense variant, predicted to cause haploinsufficient production of all hNp isoforms. Haploinsufficient Nptn^+/- mice displayed reduced levels of Np and PMCA and exhibited altered social behavior. Insufficient Np55/65 production in neurons resulted in reduced PMCA expression and function. Two missense variants caused particular structural and thermodynamic abnormalities and lower expression of hNps in human embryonic kidney (HEK) cells. In primary neurons, these hNp variants failed to regulate cytosolic Ca²⁺ transients. In Drosophila, a missense mutation affecting the PMCA interaction failed to prevent the lethal phenotype caused by hNp ortholog elimination.</p><p><strong>Conclusions: </strong>We show that a novel neurodevelopmental disorder characterized by intellectual disability and autism originates from haploinsufficient NPTN gene dosage or insufficient functionality of mutant hNp related to PMCA hypofunction.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13321906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368134","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":"Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.","authors":"Ivan Sokirniy, Zeyu Yang, Justin Pritchard","doi":"10.1186/s13073-026-01679-x","DOIUrl":"10.1186/s13073-026-01679-x","url":null,"abstract":"<p><strong>Background: </strong>Drug resistance is a constantly evolving challenge. The allosteric inhibitor asciminib is a novel therapy for chronic myelogenous leukemia (CML) that targets the myristoyl pocket of the BCR::ABL1 kinase. While it can overcome resistance to active-site inhibitors like imatinib, new resistance mutations to asciminib are emerging. The complete landscape of these mutations, particularly those outside the kinase domain or those arising from epistatic interactions between mutations, are not well understood.</p><p><strong>Methods: </strong>This study employed a dual functional genomics approach in CML cell line models. A high-throughput adenosine base editing (ABE) screen was used to identify broad hotspots of asciminib resistance across the entire BCR::ABL1 protein. Deep mutational scanning (DMS) was then used to create a high-resolution map of all possible amino acid changes within these hotspots. An \"edit-on-edit\" screen was performed to investigate epistasis by introducing a library of mutations into a cell line that was pre-edited to incorporate the common imatinib-resistance mutation, Y253H. Finally, a novel Förster resonance energy transfer (FRET) biosensor was developed to measure the conformational state of BCR::ABL1 in live cells and link it to drug sensitivity.</p><p><strong>Results: </strong>The screens identified 279 asciminib resistance mutations and revealed resistance hotspots distributed across the SH3, SH2, and kinase domains, in contrast to imatinib resistance, which is largely confined to the kinase domain. The study uncovered a potent epistatic interaction between a mutation in the SH3 domain (V73A) and a mutation in the kinase domain P-loop (Y253H), which synergistically conferred high-level resistance. The FRET biosensor demonstrated that asciminib resistance mutations tend to destabilize the \"closed\" inactive conformation of the ABL1 kinase.</p><p><strong>Conclusions: </strong>The landscape of asciminib resistance is broader and more complex than previously appreciated, involving mutations across multiple domains that disrupt ABL1 autoinhibition. Epistasis between mutations acquired during sequential therapies can create unexpected and potent resistance. However, these diverse genetic resistance mechanisms converge on a single biophysical measurement of the openness of the active ABL1 conformation. This provides a unified framework for understanding asciminib resistance and underscores the need for routine clinical resistance monitoring to include the SH3 and SH2 domains in first line and later line therapy.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13422289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338453","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":"ESR1 mutations and CDK4/6 inhibitor choice shape clonal selection and adaptive cell states during acquired resistance.","authors":"Cristina Guarducci, Daniel Abravanel, Douglas Russo, Kavya Prasad, Jingxin Fu, Zsuzsanna Nagy, Vishwajit Rao, Agostina Nardone, Yanan Kuang, Avery Feit, Wen Ma, Gabriella Cohen Feit, Francisco Hermida-Prado, Capucine Heraud, Miguel Munoz Gomez, Diana Elisa Garcia Cortes, Patrick Kurnia, Jorge Gomez Tejeda Zanudo, Rong Li, Xintao Qiu, Simona Cristea, Ariel Feiglin, Yu-Chen Cheng, Nancy U Lin, Sara M Tolaney, Luca Malorni, Piotr Sicinski, Kornelia Polyak, Cloud Paweletz, Henry Long, Chip Stewart, Franziska Michor, Gad Getz, Myles Brown, Rinath Jeselsohn","doi":"10.1186/s13073-026-01690-2","DOIUrl":"10.1186/s13073-026-01690-2","url":null,"abstract":"<p><strong>Background: </strong>In estrogen receptor-positive (ER +) breast cancer, CDK4/6 inhibitors (CDK4/6is) combined with endocrine therapy (ET) are standard first-line treatment for metastatic disease. However, most patients eventually develop resistance. Activating ESR1 mutations are a prevalent mechanism of acquired resistance to ET and are enriched after ET plus a CDK4/6 inhibitor (CDK4/6i), but their role in the clonal evolution and adaptive mechanisms of acquired resistance to CDK4/6 inhibition, independent of ET, is unknown. In addition, whether different CDK4/6is impose distinct selective pressures and divergent resistance states remains elusive.</p><p><strong>Methods: </strong>To investigate the clonal dynamics, cell states and cellular plasticity during acquired CDK4/6i resistance in mutant versus wild-type (WT) ESR1, we performed high-complexity DNA barcoding (ClonTracer library) with longitudinal sampling and multi-omic profiling in an isogeneic MCF7 model expressing WT ER or Y537S mutant ER. We also evaluated the clonality of the ESR1 mutations in clinical samples with CDK4/6i resistance.</p><p><strong>Results: </strong>We showed that ESR1 mutations are enriched in clinical tumors with acquired resistance to CDK4/6is, and in paired biopsies expanded to near clonality after treatment. We demonstrated progressive clonal selection with both divergent and partially convergent evolutionary trajectories. The ESR1 mutation substantially reshapes clonal and epigenetic evolution during palbociclib resistance but had a weaker impact under abemaciclib selection. Overall, clonal evolution and cell states in palbociclib and abemaciclib resistance were distinct. Single-cell RNA-seq revealed transcriptional heterogeneity highlighting cellular plasticity during passaging of cells and selection. Finally, in vivo barcoding of mammary xenograft, local recurrences, and distant metastases demonstrated site-specific clonal outgrowth in mutant ER metastases, and partial overlap between metastatic and CDK4/6i-resistant subclones, supporting the dual role of specific populations in therapeutic resistance and metastatic colonization.</p><p><strong>Conclusions: </strong>High-resolution lineage tracing and multi-omic studies demonstrate that CDK4/6i resistance is shaped by clonal selection and adaptive remodeling of cell states, with the ESR1 mutation status and the specific inhibitor acting as key determinants of evolutionary trajectories. These findings suggest that both variables should be considered when designing sequential and combination treatment strategies to overcome CDK4/6i resistance.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338407","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":"Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases.","authors":"Brian M Schilder, Kitty B Murphy, Hiranyamaya Dash, Yichun Zhang, Robert Gordon-Smith, Jai Chapman, Momoko Otani, Nathan G Skene","doi":"10.1186/s13073-026-01692-0","DOIUrl":"10.1186/s13073-026-01692-0","url":null,"abstract":"<p><strong>Background: </strong>Rare diseases (RDs) are a highly heterogeneous and underserved group of conditions. Most RDs have a strong genetic basis but their causal pathophysiological mechanisms remain poorly understood, limiting the development of targeted therapies.</p><p><strong>Methods: </strong>We systematically characterised the cell type-specific mechanisms underlying all genetically defined RD phenotypes by integrating the Human Phenotype Ontology (HPO) with whole-body single-cell transcriptomic atlases from embryonic, foetal, and adult samples. Associations were validated against orthogonal biomedical knowledge graphs and then prioritised by strength of supporting evidence, clinical severity, and gene-therapy compatibility.</p><p><strong>Results: </strong>We identified significant associations between 201 cell types and 9,575/11,028 (86.7%) phenotypes across 8,628 RDs, substantially expanding knowledge of phenotype-cell type links. Prioritisation by severity (e.g. lethality, motor or mental impairment) and gene-therapy compatibility (e.g. cell type specificity, postnatal treatability) identified candidate phenotypes and cell types for therapeutic targeting.</p><p><strong>Conclusions: </strong>We present a scalable, reproducible framework for phenome-wide, cell type-specific mechanism prediction in rare diseases, providing a major step toward systematic therapeutic development for patients across a broad spectrum of serious RDs.</p><p><strong>Software and data availability: </strong>Interactive web portal: https://neurogenomics-ukdri.dsi.ic.ac.uk/ . R packages introduced in this study: KGExplorer ( https://github.com/neurogenomics/KGExplorer ), HPOExplorer ( https://github.com/neurogenomics/HPOExplorer ), and MSTExplorer ( https://github.com/neurogenomics/MSTExplorer ). Manuscript analyses and reproducibility code: https://github.com/neurogenomics/rare_disease_celltyping .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13411100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338413","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":"Tumor-naïve ctDNA detection with deep learning-enhanced error suppression for sensitive mutation calling.","authors":"Shaya Akbarinejad, Sarah Doppler, Jos de Graaf, Jelena Pistolic-Kraft, Valesca Bukur, Christian Albrecht, Nathalie Buchholz, Simge Özenoglu, Ugur Sahin, Jonas Ibn-Salem, David Weber","doi":"10.1186/s13073-026-01694-y","DOIUrl":"10.1186/s13073-026-01694-y","url":null,"abstract":"<p><strong>Background: </strong>Circulating tumor DNA (ctDNA) detection offers minimally invasive monitoring of cancer from blood samples. While tumor-informed approaches are sensitive, their clinical application is limited by cost, tissue availability, and turnaround time. In contrast, tumor-naïve assays offer faster turnaround times and broader applicability, but often sacrifice sensitivity.</p><p><strong>Methods: </strong>Here, we developed DEEPctMUT, a computational pipeline for tumor-naïve ctDNA detection that integrates unique molecular identifiers (UMIs) with three complementary error-polishing strategies: (1) machine learning-based sequencing error suppression, (2) deep learning-based background noise filtering (DeepES), and (3) removal of clonal hematopoietic and germline variants using patient matched PBMC. We designed an efficient sequencing panel and developed and validated DEEPctMUT using cell lines, spike-in samples, healthy, and CRC plasma samples.</p><p><strong>Results: </strong>DEEPctMUT accurately detected mutations down to 0.03% variant allele frequency (VAF), outperforming other tumor-naïve methods. In a head-to-head comparison, our pipeline identified pre-surgical CRC cases with 100% sensitivity, whereas the Roche Avenio Surveillance Kit achieved only 50% sensitivity. Furthermore, a panel-independent version of DEEPctMUT could improve the performance of Roche Avenio data without additional assay-specific training. We provide an extensive ground-truth dataset and make DEEPctMUT, including all trained models, available as an easy-to-use Nextflow pipeline.</p><p><strong>Conclusions: </strong>By using advanced computational error-polishing techniques, DEEPctMUT can substantially reduce technical artifacts, allowing our tumor-naïve method to achieve a sensitivity comparable to tumor-informed approaches.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301539","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":"Microbial cell-free DNA for rapid pathogen identification in clinical diagnostics: a proof of concept study.","authors":"Micha Banz, Stefan Hagel, Sebastian Freiburger, Frederik Huhn, Merlin Krause, Stefan Glöckner, Bettina Löffler, Dennis Nurjadi, Uthayakumar Muthukumarasamy, Mateusz Jundzill, Achim J Kaasch, Mathias W Pletz, Christian Brandt","doi":"10.1186/s13073-026-01700-3","DOIUrl":"10.1186/s13073-026-01700-3","url":null,"abstract":"<p><p>Microbial cell-free DNA (mcfDNA) enables rapid and sensitive pathogen detection via direct plasma-sequencing. Here, we present a fast, cost-effective mcfDNA multiplex workflow to complement or improve the sensitivity of microbiological diagnostics for systemic and focal infections which can be challenged by prior antibiotic treatment or non-culturable pathogens. In an explorative study of 18 patients, mcfDNA sequencing matched the clinical diagnosis in 16 cases (89%), was detected up to 16 days after starting targeted antibiotic therapy and identified Staphylococcus aureus in two cases of culture-negative endocarditis. By providing an open-access protocol, we aim to promote broader accessibility and globally available application.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283427","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}