Genome Medicine最新文献

{"title":"A quantitative, Bayesian-informed approach to gene-specific variant classification: Updated Expert Panel recommendations improve classification of TP53 germline variants for Li-Fraumeni syndrome.","authors":"Cristina Fortuno, Megan N Frone, Jessica Mester, Miguel de la Hoya, Phuong L Mai, Tina Pesaran, Maria Isabel Achatz, Rebecca Bassett, Carolina Bustamante, Stephanie Crowley, Kelvin Cesar de Andrade, D Gareth Evans, Bingjian Feng, Laura Fuqua, Maria Isabel Harrell, Jessica N Hatton, Robert Huether, Chimene Kesserwan, Kristy Lee, Suzanne P MacFarland, Jamie L Maciaszek, Kara Maxwell, Kelly McGoldrick, Maureen Murphy, Bita Nehoray, Judith Penkert, Emilia Modolo Pinto, Sharon E Plon, Alison Schwartz-Levine, Ashley S Thompson, Wenyi Wang, Gerard P Zambetti, Kristin Zelley, Paul A James, Sharon A Savage, Christian P Kratz, Amanda B Spurdle","doi":"10.1186/s13073-025-01536-3","DOIUrl":"https://doi.org/10.1186/s13073-025-01536-3","url":null,"abstract":"<p><strong>Background: </strong>Germline pathogenic variants in TP53 cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of TP53 variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen TP53 Variant Curation Expert Panel (VCEP) has updated its specifications.</p><p><strong>Methods: </strong>The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of clonal hematopoiesis. Whenever feasible, the VCEP followed a data-driven approach using likelihood ratio-based quantitative analyses to guide code application and determine strength modifications, while also factoring in expert judgment. Proposed modifications were first discussed in working group meetings and then subjected to comprehensive review during monthly general VCEP meetings to reach consensus.</p><p><strong>Results: </strong>The performance of new specifications was compared to that of the old specifications for 43 pilot variants, and led to both decreased VUS and increased certainty, with clinically meaningful classifications for 93% of variants.</p><p><strong>Conclusions: </strong>The updated TP53 specfications are expected to reduce VUS rates, increase inter-laboratory concordance, and improve medical management for individuals with germline TP53 variants. The most current version is available at the ClinGen Criteria Specifications Registry (CSpec): https://cspec.genome.network/cspec/ui/svi/svi/GN009 .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"128"},"PeriodicalIF":10.4,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344676","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":"Polygenic risk for Alzheimer's disease in healthy aging: age-related and APOE-driven effects on brain structures and cognition.","authors":"Hao-Jie Chen, Xinyi Dong, Yichen Wang, Kexin Wang, Guozheng Feng, Tianyu Bai, Mingkai Zhang, Kaiyu Gan, Jun-Jie Peng, Weijie Huang, Zhanjun Zhang, Ni Shu, Guolin Ma","doi":"10.1186/s13073-025-01548-z","DOIUrl":"10.1186/s13073-025-01548-z","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive decline with age. The genetic architecture of AD involves multiple loci, including the apolipoprotein E gene (APOE). The polygenic risk scores for AD (AD-PRS) provide a comprehensive genome-wide assessment of AD risk, yet their age-related effects on brain structures and cognitive function in cognitively unimpaired individuals remain largely undefined.</p><p><strong>Methods: </strong>We analyzed cognitively unimpaired, genetically unrelated Caucasians from the UK Biobank (N = 21,236, 64.5 ± 7.6 years). AD-PRS was derived using a Bayesian approach incorporating approximately 5 million genetic variants (UK Biobank's standard PRS). Brain structures were measured with regional gray matter (GM) volumes and tract-wise microstructural white matter (WM) integrity. Cognitive performance was evaluated with executive function, visuospatial function, reasoning, and memory. Sliding window analyses were performed to investigate age-related polygenic effects on brain structures, and mediation analyses tested whether structural changes mediated the gene-cognition relationship across different age groups. Analyses were replicated using two custom PRSs-one including APOE and the other excluding APOE regions-calculated with the clumping-and-thresholding approach.</p><p><strong>Results: </strong>High AD-PRS was associated with accelerated GM atrophy (particularly in the hippocampus, thalamus, and parahippocampus), increased cerebral ventricular volume, and reduced WM integrity (especially in the fornix, cingulum, and superior fronto-occipital fasciculus). These polygenic effects demonstrated significant age-related amplification (p_Bonf < 0.05), with the strongest effects in individuals aged ≥ 75. Elevated AD-PRS was linked to lower cognitive performance across aging, especially in executive function, reasoning, and memory, which were significantly mediated by structural brain changes in subcortical and posterior limbic regions and their WM connections, predominantly in late aging (p < 0.05). Sensitivity analyses confirmed the robustness of these findings, emphasizing the dominant contribution of APOE, while also identifying age-specific effects from non-APOE variants.</p><p><strong>Conclusions: </strong>High polygenic risk for AD may be associated with accelerated cognitive decline in healthy aging, mediated by structural changes within hippocampal-thalamic regions and their connecting WM tracts. We provide insights into the early pathogenesis of AD and support the potential for age-targeted screening and early intervention for individuals at high genetic risk.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"126"},"PeriodicalIF":10.4,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12539216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344677","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":"An optimized variant prioritization process for rare disease diagnostics: recommendations for Exomiser and Genomiser.","authors":"Isabelle B Cooperstein, Shruti Marwaha, Alistair Ward, Shilpa N Kobren, Jennefer N Carter, Matthew T Wheeler, Gabor T Marth","doi":"10.1186/s13073-025-01546-1","DOIUrl":"10.1186/s13073-025-01546-1","url":null,"abstract":"<p><strong>Background: </strong>Exome sequencing (ES) and genome sequencing (GS) are increasingly used as standard genetic tests to identify diagnostic variants in rare disease cases. However, prioritizing these variants to reduce the time and burden of manual interpretation by clinical teams remains a significant challenge. The Exomiser/Genomiser software suite is the most widely adopted open-source software for prioritizing coding and noncoding variants. Despite its ubiquitous use, limited data-driven guidelines currently exist to optimize its performance for diagnostic variant prioritization. Based on detailed analyses of Undiagnosed Diseases Network (UDN) probands, this study presents optimized parameters and practical recommendations for deploying the Exomiser and Genomiser tools. We also highlight scenarios where diagnostic variants may be missed and propose alternative workflows to improve diagnostic success in such complex cases.</p><p><strong>Methods: </strong>We analyzed 386 diagnosed probands from the UDN, including cases with coding and noncoding diagnostic variants. We systematically evaluated how tool performance was affected by key parameters, including gene:phenotype association data, variant pathogenicity predictors, phenotype term quality and quantity, and the inclusion and accuracy of family variant data.</p><p><strong>Results: </strong>Parameter optimization significantly improved Exomiser's performance over default parameters. For GS data, the percentage of coding diagnostic variants ranked within the top 10 candidates increased from 49.7% to 85.5%, and for ES, from 67.3% to 88.2%. For noncoding variants prioritized with Genomiser, the top 10 rankings improved from 15.0% to 40.0%. We also explored refinement strategies for Exomiser outputs, including using p-value thresholds and flagging genes that are frequently ranked in the top 30 candidates but rarely associated with diagnoses.</p><p><strong>Conclusion: </strong>This study provides an evidence-based framework for variant prioritization in ES and GS data using Exomiser and Genomiser. These recommendations have been implemented in the Mosaic platform to support the ongoing analysis of undiagnosed UDN participants and provide efficient, scalable reanalysis to improve diagnostic yield. Our work also highlights the importance of tracking solved cases and diagnostic variants that can be used to benchmark bioinformatics tools. Exomiser and Genomiser are available at https://github.com/exomiser/Exomiser/ .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"127"},"PeriodicalIF":10.4,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12539062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344698","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":"HLA-DRB1*15:01 is associated with a reduced likelihood of longevity in northern European men.","authors":"Nicolás Mendoza-Mejía, Daniel Kolbe, Onur Özer, Janina Dose, Guillermo G Torres, Andre Franke, Marianne Nygaard, Almut Nebel","doi":"10.1186/s13073-025-01554-1","DOIUrl":"10.1186/s13073-025-01554-1","url":null,"abstract":"<p><strong>Background: </strong>Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. Here, we addressed this gap by analysing the influence of HLA variation on longevity in Europeans.</p><p><strong>Methods: </strong>We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Associations were evaluated with logistic regression, adjusting for multiple testing and population structure. Subsequently, significant associations (adjusted P ≤ 0.05) were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank. Furthermore, epitope binding and immunogenicity predictions were performed to detect potential mechanisms linking HLA alleles to longevity.</p><p><strong>Results: </strong>Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity (adjusted P = 2.80 × 10^-2, odds ratio = 0.64, 95% CI: 0.48-0.82). In Germans, HLA-DRB1*15:01:01 was less frequent among male cases (10%) than controls (15%), whilst female cases exhibited no substantial decrease (14%), suggesting that men carrying this allele have a lower chance of becoming long-lived. This finding was replicated in the UK Biobank and found to be consistent in the Danish cohort. Computational predictions further revealed that HLA-DRB1*15:01 is more likely to trigger an immune response against an apolipoprotein B-100 (APOB-100) epitope than other HLA-DRB1 alleles. Furthermore, the overall predicted APOB-100 immunogenicity of all HLA-DRB1 alleles was significantly associated with longevity (estimate -0.11, SE = 0.03, P = 0.005).</p><p><strong>Conclusions: </strong>The novel male-specific association between HLA-DRB1*15:01 and longevity has been observed in three independent cohorts. The anti-longevity effect of this association is perhaps a consequence of an increase in Alzheimer's disease (AD)-related mortality in men carrying this allele. This hypothesis is based on prior research that has identified a male-specific association between HLA-DRB1*15:01:01 and AD. Additionally, it is likely that this link is mediated by increased immune reactivity against APOB-100, which is promoted by HLA-DRB1*15:01:01.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"125"},"PeriodicalIF":10.4,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12539080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336849","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":"Proteomic landscape of multidimensional aging phenotypes.","authors":"Zhi Cao, Han Chen, Jiahao Min, Chenjie Xu","doi":"10.1186/s13073-025-01558-x","DOIUrl":"10.1186/s13073-025-01558-x","url":null,"abstract":"<p><strong>Background: </strong>Proteomic signatures of aging hold promise for advancing our understanding of aging evaluation and guiding targeted therapy. Despite this potential, the proteomic landscape of multidimensional aging phenotypes remains inadequately characterized. We aimed to identify the potential proteomic biomarkers of aging process and decipher their molecular mechanisms.</p><p><strong>Methods: </strong>We analyzed 2920 plasma proteomic biomarkers from 48,728 participants in the UK Biobank. The multidimensional aging phenotypes included Klemera and Doubal's method biological age (KDM-BA) acceleration, PhenoAge acceleration, frailty index, leukocyte telomere length (LTL), and healthspan. Two-sample Mendelian randomization (MR) analyses were performed to determine the causal effect of plasma proteome on the multidimensional aging phenotypes, and replicate the identified proteomic signatures in the FinnGen cohort. Multivariable linear regressions were used to explore the phenotypic associations between plasma proteome and multidimensional aging phenotypes. We then applied a series of bioinformatic approaches to elucidate the biological function and drug targets of the identified proteins. Multi-omics data were further leveraged to decipher the genetic mechanisms and metabolic pathways of aging process.</p><p><strong>Results: </strong>We found that genetically determined levels of 17, 37, 12, 18, and 1 proteins were causally linked to KDM-BA acceleration, PhenoAge acceleration, frailty index, LTL, and healthspan, respectively. Replication in the FinnGen cohort confirmed a subset of these associations. We observed significant phenotypic associations for 2,186, 2,152, 1,459, 668, and 545 proteins with KDM-BA acceleration, PhenoAge acceleration, frailty index, LTL, and healthspan, respectively. Our integrative analysis identified 71 distinct plasma proteins associated with multidimensional aging phenotypes, of which 12 are promising candidates for drug targeting, primarily involved in inflammatory processes and cellular senescence. Moreover, we identified 22 genetic variants that may regulate these protein abundances in the context of aging, complemented by metabolomic profiling that highlights several metabolic pathways mediating the proteins and aging.</p><p><strong>Conclusions: </strong>Our findings facilitate a more comprehensive understanding of the proteomic landscape of the multidimensional aging phenotypes, thereby providing an opportunity for personalized monitoring of aging and effective therapeutic strategies in aging-related diseases.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"122"},"PeriodicalIF":10.4,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312618","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":"Novel multiplex family-wide PCR and Nanopore sequencing of amplicons (FP-NSA) approach for surveillance of influenza- and coronaviruses in humans and animals.","authors":"Irene Kasindi Meki, Ki Bum Ahn, William G Dundon, Tirumala Bharani K Settypalli, Christoph Leth, Adi Steinrigl, Sandra Revilla-Fernández, Friedrich Schmoll, Letizia Ceglie, Kouramoudou Berete, Artem Metlin, Madhur Dhingra, Norbert Nowotny, Giovanni Cattoli, Charles Euloge Lamien","doi":"10.1186/s13073-025-01550-5","DOIUrl":"10.1186/s13073-025-01550-5","url":null,"abstract":"<p><strong>Background: </strong>Recent outbreaks of zoonotic diseases like Ebola, Mpox, dengue fever, and COVID-19 highlight gaps in surveillance and early detection at disease hotspots. Virus family-wide diagnostic assays offer a cost-effective and sensitive alternative to metagenomics for initial virus identification. This study introduces a multiplex family-wide PCR coupled with Nanopore sequencing of amplicons (FP-NSA) for surveillance of novel and known zoonotic respiratory viruses, including influenza A and D viruses (IAV and IDV), alpha (α-), beta (β-), and gamma (γ-) coronaviruses (CoVs).</p><p><strong>Methods: </strong>This assay utilized primers in conserved regions of each virus group for multiplex reverse transcription (RT)-PCR coupled with the portable MinION device for rapid Nanopore sequencing. The FP-NSA was optimized using seven IAV subtypes, IDVs, and α- and β-CoVs. The analytical sensitivity of the FP-NSA was assessed using positive controls of known concentrations from each targeted viral family and validated using clinical samples and cell culture isolates from various host species and geographical origins. Potential novel viruses detected in the clinical samples, based on the FP-NSA, were further analyzed using metagenomics sequencing with the Sequence-Independent Single Primer Amplification (SISPA) approach.</p><p><strong>Results: </strong>The optimized FP-NSA assay efficiently detected all the targeted viruses singly as well as in co-infection scenarios of multiple respiratory viruses. Evaluation of the assay on 78 selected clinical and cell culture samples (from 184 initially screened) successfully detected IAVs; α-CoVs: porcine epidemic diarrhea virus (PEDV), human coronavirus (HCoV) NL63, and HCoV-229E; β-CoVs: HCoV-OC43, severe acute respiratory syndrome (SARS)-CoV-(1), SARS-CoV-2, and MERS-CoV; and γ-CoV infectious bronchitis virus (γ-CoV_IBV) infections. Additionally, the FP-NSA assay discovered a novel γ-CoV_IBV from Guinea that is phylogenetically distant from known genotypes using a SISPA metagenomics approach.</p><p><strong>Conclusions: </strong>The assay's short PCR amplicons enable screening of samples within 4 h, from PCR to sequencing and bioinformatics analysis, providing an adequate number of pathogens' reads. The portable MinION device makes the assay suitable for pathogen surveillance in disease hotspots and resource-limited regions such as low- and middle-income countries. Thus, the FP-NSA assay is a valuable tool for detecting potential novel and known zoonotic respiratory viruses in the targeted families across various host species.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"123"},"PeriodicalIF":10.4,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312646","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":"Recommendations for bioinformatics in clinical practice.","authors":"Ksenia Lavrichenko, Emilie Sofie Engdal, Rasmus L Marvig, Anders Jemt, Jone Marius Vignes, Henrikki Almusa, Kristine Bilgrav Saether, Eiríkur Briem, Eva Caceres, Edda María Elvarsdóttir, Magnús Halldór Gíslason, Maria K Haanpää, Viktor Henmyr, Ronja Hotakainen, Eevi Kaasinen, Roan Kanninga, Sofia Khan, Mary Gertrude Lie-Nielsen, Majbritt Busk Madsen, Niklas Mähler, Khurram Maqbool, Ramprasad Neethiraj, Karl Nyrén, Minna Paavola, Peter Pruisscher, Ying Sheng, Ashish Kumar Singh, Aashish Srivastava, Thomas K Stautland, Daniel T Andreasen, Esmee Ten Berk de Boer, Søren Vang, Valtteri Wirta, Frederik Otzen Bagger","doi":"10.1186/s13073-025-01543-4","DOIUrl":"10.1186/s13073-025-01543-4","url":null,"abstract":"<p><strong>Background: </strong>Next-generation sequencing (NGS) is well established in clinical diagnostics, and whole-genome sequencing (WGS) is increasingly becoming the method of choice, as a result of lower prices and robust comprehensive data. While guidelines exist for variant interpretation and laboratory quality considerations, there remains a need for standardised bioinformatics practices to ensure clinical consensus, accuracy, reproducibility and comparability.</p><p><strong>Methods: </strong>This article presents consensus recommendations developed by 13 clinical bioinformatics units participating in the Nordic Alliance for Clinical Genomics (NACG) by expert bioinformaticians working in clinical production. The recommendations are based on clinical practice and focus on analysis types, test and validation, standardisation and accreditation, as well as core competencies and technical management required for clinical bioinformatics operations.</p><p><strong>Results: </strong>Key recommendations include adopting the hg38 genome build as reference, and a standard set of recommended analyses, including the use of multiple tools for structural variant (SV) calling and in-house data sets for filtering recurrent calls. Clinical bioinformatics in production should operate at standards similar to ISO 15189, utilising off-grid clinical-grade high-performance computing systems, standardised file formats and strict version control. Reproducibility should be ensured through containerised software environments. Pipelines must be documented and tested for accuracy and reproducibility, minimally covering unit, integration and end-to-end testing. Standard truth sets such as GIAB and SEQC2 for germline and somatic variant calling, respectively, should be supplemented by recall testing of real human samples that have been previously tested using a validated method. Data integrity must be verified using file hashing, while sample identity must be confirmed through fingerprinting and genetically inferred identification markers such as sex and relatedness. Finally, clinical bioinformatics should encompass diverse skills, including software development, data management, quality assurance and domain expertise in human genetics.</p><p><strong>Conclusions: </strong>These recommendations provide a consensus framework for standardising bioinformatics practices across clinical WGS applications and can serve as a practical guide to facilities that are new to large-scale sequencing-based diagnostics, or as a reference for those who already run high-volume clinical production using NGS.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"124"},"PeriodicalIF":10.4,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312722","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":"Epigenetic profiles of tissue informative CpGs inform ALS disease status and progression.","authors":"Christa Caggiano, Marco Morselli, Xiaoyu Qian, Barbara Celona, Michael J Thompson, Shivangi Wani, Anela Tosevska, Kodi Taraszka, Galen Heuer, Shyuan T Ngo, Frederick J Steyn, Peter J Nestor, Leanne Wallace, Pamela McCombe, Susan Heggie, Kathryn Thorpe, Caitlin McElligott, Gemyka English, Anjali Henders, Robert Henderson, Catherine Lomen-Hoerth, Naomi R Wray, Allan F McRae, Matteo Pellegrini, Fleur C Garton, Noah Zaitlen","doi":"10.1186/s13073-025-01542-5","DOIUrl":"10.1186/s13073-025-01542-5","url":null,"abstract":"<p><strong>Background: </strong>Cell-free DNA (cfDNA), derived from dying cells, has demonstrated utility across multiple clinical applications. However, its potential in neurodegenerative diseases remains underexplored, with most existing cfDNA technologies tailored to specific disease contexts like cancer or non-invasive prenatal screening.</p><p><strong>Methods: </strong>To address this gap, we developed a novel approach to characterize epigenetic cfDNA profiles by identifying key regions of DNA methylation that reveal the tissues origins undergoing apoptosis or necrosis. We evaluated this method in the largest cfDNA study of amyotrophic lateral sclerosis (ALS) and other neurological diseases (OND) to date, encompassing two independent cohorts (n = 192) from Australia (UQ N_cases = 48, N_controls = 32, N_OND = 15) and the USA, (UCSF N_cases = 50, N_controls = 45)).</p><p><strong>Results: </strong>Our approach accurately distinguished ALS patients from controls (UQ AUC = 0.82, UCSF AUC = 0.99) and from individuals with other neurological diseases (AUC = 0.91). It also identified an asymptomatic carrier of a pathogenic C9orf72 variant, and strongly correlated with ALS disease progression measures (Pearson's R = 0.66, p = 3.71 × 10⁻⁹).</p><p><strong>Conclusions: </strong>We identified DNA methylation signals from multiple tissue types in ALS cfDNA, highlighting diverse tissue involvement in ALS pathology. These findings promote epigenetic cfDNA analysis as a powerful tool for advancing our understanding of neurodegenerative disease.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"115"},"PeriodicalIF":10.4,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12529837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299850","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":"A human YEATS4 variant confers resistance to TST and IGRA conversion despite Mycobacterium tuberculosis exposure.","authors":"Clément Conil, Jonathan Bohlen, Elouise E Kroon, Marc A Jean-Juste, Jérémy Manry, Matthieu Chaldebas, James M Bean, Kathleen F Walsh, Monica Dallmann-Sauer, Maxime Rotival, Yoann Seeleuthner, Astrid Marchal, Haralambos Mourelatos, Vinicius M Fava, Peng Zhang, Gaspard Kerner, Hanaa Skhoun, Ahmed Abid, Hanane El Ouazzani, Aniss Rafik, Ahmed Aziz Bousfiha, Jamila El Baghdadi, Robert J Wilkinson, Stéphanie Boisson-Dupuis, Daniel W Fitzgerald, Jean W Pape, Marlo Möller, Eileen G Hoal, Jean-Laurent Casanova, Laurent Abel, Erwin Schurr, Aurélie Cobat","doi":"10.1186/s13073-025-01547-0","DOIUrl":"10.1186/s13073-025-01547-0","url":null,"abstract":"<p><strong>Background: </strong>Despite sustained exposure to Mycobacterium tuberculosis (Mtb), some individuals-so-called resisters-have persistently negative results for the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). \"Resistance to immune conversion\" is the best-known clinical correlate for absence of Mtb transmission and protection from tuberculosis (TB). We investigated the human genetic basis of this phenotype by hypothesizing that resisters living with HIV, a major risk factor for TB, would be enriched in genotypes conferring resistance.</p><p><strong>Methods: </strong>We enrolled two cohorts of people living with HIV (PWH), consisting of 55 resisters and 100 controls-either positive for TST and IGRA or with a history of TB-from South Africa, and 66 resisters and 57 controls from Haiti, two regions where TB is hyperendemic. All study participants underwent whole-genome sequencing (WGS). We performed a genome-wide association study (GWAS) of the resister phenotype, focusing on a comprehensive set of 320,629 common protein-altering and regulatory variants.</p><p><strong>Results: </strong>We identified a cluster of variants on chromosome 12q15, including rs622656, associated with the resister phenotype in both South Africa and Haiti. A meta-analysis revealed that the C allele of rs622656 was associated with the resister phenotype with an odds ratio (OR) of 4.35 (95% CI: 2.44-7.69) (P = 2.47 × 10^-7). The frequency of the C allele in the combined sample was 0.11, and all four CC homozygotes in our sample were resisters. Consistently, we found a significant depletion of homozygous carriers of the rs622656-C resistance-associated allele in three cohorts of HIV-negative TB patients from Haiti, Morocco, and the UK Biobank. In silico analysis suggested that the rs622656-C resistance-associated allele increased the translation of the nearby YEATS4 gene by suppressing an upstream open reading frame. YEATS4 has been shown to play a role in innate lymphoid cell differentiation, a leukocyte subset. We confirmed experimentally that the rs622656-C resistance-associated allele increased the activity of the reporter gene in HEK293T cells.</p><p><strong>Conclusions: </strong>We report a new cluster of variants on chromosome 12q15, overlapping the YEATS4 gene, strongly associated with the resister phenotype in two populations of PWH. Our results contribute to the understanding of the molecular mechanisms that block transmission of Mtb.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"121"},"PeriodicalIF":10.4,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299767","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":"Genomic characterisation of recurrent Mycobacterium avium isolates from chronically infected patients reveals patterns of within-host evolution.","authors":"Aaron M Walsh, Emma Roycroft, Kate Hinchion, Sharee A Basdeo, Frederick J Sheedy, Fiona Crispie, Paul D Cotter, Anne Marie McLaughlin, Joseph Keane, Margaret M Fitzgibbon, Laura E Gleeson","doi":"10.1186/s13073-025-01549-y","DOIUrl":"10.1186/s13073-025-01549-y","url":null,"abstract":"<p><strong>Background: </strong>Mycobacterium avium complex causes chronic and difficult-to-treat infection in vulnerable patient groups, and incidence is increasing worldwide. Whole genome sequencing has the potential to reveal new information about how M. avium persists over time in the human lung.</p><p><strong>Methods: </strong>We analysed the genomes of 287 isolates of M. avium that were sampled longitudinally from 56 patients. Our dataset included 50 newly sequenced genomes from a cohort of 20 patients from Ireland who were sampled for up to 10 years, and we compared these to 237 published genomes from 2 pre-existing cohorts from Europe to evaluate strains from Ireland in a wider context. Additionally, we performed a combined analysis across the 3 cohorts to examine the changes that occurred over the course of infection.</p><p><strong>Results: </strong>We identified 2 instances where strains from Ireland clustered with strains from Europe within a 13-SNP threshold, supporting previous observations that dominant circulating clones of M. avium are present internationally. Across the 3 cohorts, we found that the communities of M. avium evolved over time within individual hosts, and we report that acquisition of new strains is frequent. Importantly, our findings suggest that M. avium may adapt to the conditions that it faces in the host, with evidence of positive selection of 13 distinct mycobacterial genes. Notably, multiple virulence-associated genes were under selection, including genes that could confer resistance to antibiotics and host defence mechanisms.</p><p><strong>Conclusions: </strong>Whole genome sequencing provides novel insights into within-host evolution of M. avium and highlights potentially important mycobacterial strategies to enhance persistence that may provide new targets for therapeutic investigation.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"120"},"PeriodicalIF":10.4,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285939","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}