Genome Medicine最新文献

{"title":"Identification of a PRDM1-regulated T cell network to regulate atherosclerotic plaque inflammation.","authors":"Han Jin, Sanne L Maas, Yuchi Zou, Chang Lu, Baixue Yu, Rosanna Huchzermeier, Samantha Nadeau, Jessica Dos Santos, Marion Gijbels, Barend M E Mees, Evgueni Smirnov, Ljubica Matic, Ulf Hedin, Pasquale Maffia, Claudia Monaco, Judith C Sluimer, Gislâine A Martins, Emiel P C van der Vorst, Erik A L Biessen","doi":"10.1186/s13073-025-01541-6","DOIUrl":"https://doi.org/10.1186/s13073-025-01541-6","url":null,"abstract":"<p><strong>Background: </strong>Inflammation is a key driver of atherosclerosis, yet the mechanisms sustaining inflammation in human plaques remain poorly understood. This study uses a network-based approach to identify immune gene programs involved in the transition from low- to high-risk (rupture-prone) human atherosclerotic plaques.</p><p><strong>Methods: </strong>Expression data from human carotid artery plaques, both stable (low-risk, n = 16) and unstable (high-risk, n = 27), were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA). Bayesian network inference, operated on the eigengene values from the WGCNA, further extended the WGCNA analysis, and similarity to the signature of T cell subsets was validated in single-cell RNA sequencing data of human plaques, and a loss-of-function study in a mouse model of atherosclerosis. In silico drug repurposing was performed to identify potential therapeutic targets.</p><p><strong>Results: </strong>Our analysis revealed a distinct gene module with a prominent T cell signature, particularly in unstable plaques. Key regulatory factors, RUNX3, IRF7 and in particular PRDM1, were significantly downregulated in plaque T cells from symptomatic versus asymptomatic patients, indicating a protective role. Additionally, as PRDM1 is downstream of IRF7, we opted for PRDM1 as a key target. T cell-specific Prdm1 deficiency in Western-type diet fed Ldlr knockout mice featured accelerated plaque progression. Finally, as PRDM1 targeting drugs are not yet available, we performed in silico drug repurposing, identifying EGFR inhibitors as promising therapeutic candidates.</p><p><strong>Conclusions: </strong>This study highlights a PRDM1-regulated T cell network that distinguishes high-risk from low-risk plaques and demonstrates the regulatory role of T cell PRDM1 in controlling atherosclerosis, positioning this pathway as a promising therapeutic target.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"109"},"PeriodicalIF":10.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212523","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":"Prematurity and genetic liability for autism spectrum disorder.","authors":"Yali Zhang, Ashraf Yahia, Sven Sandin, Ulrika Åden, Kristiina Tammimies","doi":"10.1186/s13073-025-01552-3","DOIUrl":"https://doi.org/10.1186/s13073-025-01552-3","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by diverse presentations and a strong genetic component. Environmental factors, such as prematurity, have also been linked to increased liability for ASD, though the interaction between genetic predisposition and prematurity remains unclear. This study aims to investigate the impact of genetic liability and preterm birth on ASD conditions.</p><p><strong>Methods: </strong>We analyzed phenotype and genetic data from two large ASD cohorts, the Simons Foundation Powering Autism Research for Knowledge (SPARK) and Simons Simplex Collection (SSC), encompassing 78,559 individuals for phenotype analysis, 12,519 individuals with genome sequencing data, and 8104 individuals with exome sequencing data. Statistical significance of differences in clinical measures was evaluated between individuals with different ASD and preterm status. We assessed the rare variants burden using generalized estimating equations (GEE) models and polygenic load using the ASD-associated polygenic risk score (PRS). Furthermore, we developed a machine learning model to predict ASD in preterm children using phenotype and genetic features available at birth.</p><p><strong>Results: </strong>Individuals with both preterm birth and ASD exhibit more severe phenotypic outcomes despite similar levels of genetic liability for ASD across the term and preterm groups. Notably, preterm-ASD individuals showed an elevated rate of de novo variants identified in exome sequencing (GEE model, p = 0.005) in comparison to non-ASD-preterm group. Additionally, a GEE model showed that a higher ASD PRS, preterm birth, and male sex were positively associated with a higher predicted probability for ASD in SPARK, reaching a probability close to 90%. Lastly, we developed a machine learning model using phenotype and genetic features available at birth with limited predictive power (AUROC = 0.65).</p><p><strong>Conclusions: </strong>Preterm birth may exacerbate multimorbidity present in ASD, which was not due to ASD-associated genetic variants. However, increased ASD-associated rare variants may elevate the likelihood of a preterm child being diagnosed with ASD. Additionally, a polygenic load of ASD-associated variants had an additive role with preterm birth in the predicted probability for ASD, especially for boys. Future integration of genetic and phenotypic data in larger preterm or population-based cohorts will be crucial for advancing early ASD identification in preterm subgroup.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"108"},"PeriodicalIF":10.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212485","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":"Adult genomic medicine: lessons from a multisite study of 2700 patients.","authors":"Khadijah Bakur, Halima Hamid, Bader Alhaddad, Majid Alfadhel, Amal Alhashem, Wafaa Eyaid, Talal Alanzi, Fuad Al Mutairi, Abdulrahman Alswaid, Farouq Ababneh, Malak Al Ghamdi, Sarar Mohamed, Ahmed Alaskar, Farjah Alqahtani, Hamad Alzaidan, Mohammed Al-Owain, Eissa A Faqeih, Aziza M Mushiba, Rola Alanazi, Basamat Almoallem, Norah Saleh Alsaleh, Saeed Al Tala, Muneera Alshammari, Alyazeed Turkistani, Ghadah Gosadi, Fahad Hakami, Fahad Alobaid, Hadeel Al Rukban, Ahmed Alfaidi, Rola Ba-Abbad, Mohammed A Almuqbil, Ahmad Al-Boukai, Abdulrahman Saad Alamri, Ali Alshehri, Raashda A Sulaiman, Ali Almontasheri, Enam Danish, Afaf AlSagheir, Deema Aljeaid, Bashayer S Al-Awam, Aiman Shawli, Maha Al-Otaibi, Wed Sameer Majdali, Zohor Asaad Azher, Mohammed Almannai, Wail Baalawi, Lama AlAbdi, Touati Benoukraf, Fowzan S Alkuraya","doi":"10.1186/s13073-025-01529-2","DOIUrl":"10.1186/s13073-025-01529-2","url":null,"abstract":"<p><strong>Background: </strong>Clinical exome and genome sequencing has transformed the diagnostic workup of patients with genetic disorders. The extensive body of evidence supporting the application of this clinical genomics approach in pediatric patients stands in stark contrast to the relative paucity of evidence for its use in the adult population. Here, we describe the largest cohort to date of adult patients who underwent clinical exome and genome sequencing for suspected genetic diagnoses.</p><p><strong>Methods: </strong>A total of 2763 adult patients (2529 families) from all regions of Saudi Arabia are included in this cohort (2202 exomes, and 561 genomes).</p><p><strong>Results: </strong>The diagnostic rate is 38.9% spanning 535 Mendelian genes and revealing clinical diagnostic errors in 38% of patients with positive reports. Structured feedback using C-GUIDE demonstrates clinical utility in 90% of positive cases. Consistent with the highly consanguineous nature of the local population, the majority (61%) of diagnosed phenotypes are recessive (94.6% homozygous) and founder variants account for 85% (414/487) of these variants. The same population characteristic has also led to the encounter of extremely rare, even novel recessive disorders including a highly penetrant novel RNF43-related hemochromatosis, NFXL1-related syndrome of hyperlaxity, short stature, and kidney disease, as well as autosomal recessive forms of typically dominant disorders. Multilocus phenotypes are observed in 5% of cases although only 26.7% of these are caused by two recessive variants. That 70% of molecular diagnoses encountered in our cohort are typically described in pediatric patients allowed us to observe highly unusual clinical presentations in the adult population. This delayed diagnosis also represents a missed opportunity for effective treatment in many instances and we note the availability of treatment for 26% of diagnosed conditions. Of particular interest are patients with monogenic disorders that could be overlooked as common multifactorial adult diseases (e.g., diabetes, dyslipidemia, stroke, chronic kidney disease, and dementia). Finally, we note the opportunities of deploying adult clinical genomics in an underrepresented population where 45.5% (373/819) of encountered variants are completely absent in gnomAD.</p><p><strong>Conclusions: </strong>Our results illustrate numerous benefits of a clinical genomics approach in adult medicine and argue for a broader implementation than currently practiced.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"105"},"PeriodicalIF":10.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191451","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":"Distinct patterns of genetic overlap among multimorbidities revealed with trivariate MiXeR.","authors":"Alexey A Shadrin, Guy Hindley, Espen Hagen, Nadine Parker, Markos Tesfaye, Piotr Jaholkowski, Zillur Rahman, Gleda Kutrolli, Vera Fominykh, Srdjan Djurovic, Olav B Smeland, Kevin S O'Connell, Dennis van der Meer, Oleksandr Frei, Ole A Andreassen, Anders M Dale","doi":"10.1186/s13073-025-01528-3","DOIUrl":"10.1186/s13073-025-01528-3","url":null,"abstract":"<p><strong>Background: </strong>Multimorbidities are a global health challenge. Accumulating evidence indicates that overlapping genetic architectures underlie comorbid complex human traits and disorders. This can be quantified for a pair of phenotypes using various techniques. Still, the pattern of genetic overlap between three distinct complex phenotypes, which is important for understanding multimorbidities, has not been possible to quantify.</p><p><strong>Methods: </strong>Here, we present and validate the novel trivariate MiXeR tool, which disentangles the pattern of genetic overlap between three complex phenotypes using summary statistics from genome-wide association studies. Our simulations show that trivariate MiXeR can reliably reconstruct different patterns of genetic overlap and estimate the proportions of genetic overlap between three phenotypes.</p><p><strong>Results: </strong>We found substantial genetic overlap between gastro-intestinal and brain diseases supporting a genetic basis of the gut-brain axis-the pattern consistent with pairwise analysis. However, the pattern of genetic overlap between three diverse cardiometabolic and renal health indicators and three immune-linked disorders revealed a much larger genomic component shared between all phenotypes than expected from separate pairwise analyses. This suggests the existence of core pathways underlying distinct but related chronic conditions.</p><p><strong>Conclusions: </strong>Overall, trivariate MiXeR offers a novel and efficient tool for investigating patterns of genetic overlap among three complex phenotypes. This contributes to a better understanding of genetic relationships between complex traits and disorders, potentially providing new insights into the mechanisms underlying common multimorbidities. Trivariate MiXeR is freely available at https://github.com/precimed/mix3r .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"106"},"PeriodicalIF":10.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191454","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":"Personalized transcriptional network analysis links age-related loss of gene coordination to individual biological aging.","authors":"Hao-Tian Wang, Fu-Hui Xiao, Long Zhao, Qian Su, Tian-Rui Xia, Li-Qin Yang, Si-Yu Ma, Qing-Peng Kong","doi":"10.1186/s13073-025-01533-6","DOIUrl":"10.1186/s13073-025-01533-6","url":null,"abstract":"<p><strong>Background: </strong>Aging is characterized by the decline in biological functions, accompanied by changes in gene-to-gene transcriptional coordination, which can be estimated by expression coordination in gene transcriptional network. Notably, gene networks and coordinated expression relationships (CERs) showed inter-individual variability, while personalized aging-related gene expression coordination dynamics in human cohorts have yet to be investigated.</p><p><strong>Methods: </strong>In this study, we constructed 15,933 personalized transcriptional networks across 26 tissues from 967 donors aged 20 to 80 years old, using the sample-specific network (SSN) framework based on data from the Gene-Tissue Expression (GTEx) project.</p><p><strong>Results: </strong>We identified gene-gene CERs and characterized their age-dependent dynamic trends across tissues, observing a universal trend of increased gene-to-gene coordination loss during aging across tissues. The count of lost CERs is also positively correlated with individual-level aging and senescence-related molecular phenotypes. Notably, we revealed that the lost CERs have potential as biomarkers for individual aging and health status. In addition, we identified gene coordination loss events exhibiting significant positive correlation with age, defined as aging-related lost relationships (ARLRs), which may be functionally associated with pathways related to proteolytic processes. Finally, we showed that ARLRs may contribute to deleterious effects and increased pathogenicity through gene dosage imbalances.</p><p><strong>Conclusions: </strong>This study establishes, for the first time, a connection between the loss of gene-to-gene expression coordination and individual-level aging progress. It provides proof-of-principle evidence for using lost gene coordinated expression relationships as biomarkers of healthy aging and highlights the potential risks associated with coordination loss in specific biological pathways during aging.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"104"},"PeriodicalIF":10.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174700","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":"Optimized high-throughput whole-genome sequencing workflow for surveillance of influenza A virus.","authors":"Matthias Licheri, Mike Mwanga, Manon F Licheri, Annika Graaf-Rau, Cora Sägesser, Pascal Bittel, Timm Harder, Franziska Suter-Riniker, Jenna N Kelly, Ronald Dijkman","doi":"10.1186/s13073-025-01512-x","DOIUrl":"10.1186/s13073-025-01512-x","url":null,"abstract":"<p><p>Whole-genome sequencing (WGS) is essential for monitoring the genetic diversity of influenza A virus (IAV) across host species. We optimized a multisegment RT-PCR (mRT-PCR) protocol to enhance amplification of all eight IAV segments using modified RT and PCR conditions. Additionally, we introduced a dual-barcoding approach for the Oxford Nanopore platform, enabling high-throughput multiplexing without compromising sensitivity. The resulting workflow is robust, scalable, and effective for avian, swine, and human IAV samples, even at low viral loads. This approach strengthens genomic surveillance at the human-animal interface, supporting early detection, evolutionary monitoring, and rapid identification of IAV spillover events.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"103"},"PeriodicalIF":10.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174675","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":"EMB is essential for enteric nervous system development mediated by PI3K signaling.","authors":"Zhi Li, Didi Zhuansun, Xinyao Meng, Heying Yang, Jun Xiao, Yingjian Chen, Jing Wang, Xiaosi Yu, Zejian Li, Jingyi You, Xuyong Chen, Chenzhao Feng, Luyao Wu, Xufeng Chu, Weicheng Duan, Kang Wang, Zongzhe Li, Jinfa Tou, Lei Yu, Weibing Tang, Yuanmei Liu, Xuewu Jiang, Hongxia Ren, Mei Yu, Qiang Yin, Xiang Liu, Zhilin Xu, Dianming Wu, Chunlei Jiao, Donghai Yu, Xiaojuan Wu, Tianqi Zhu, Jixin Yang, Lei Xiang, Jing Wang, Qiong Wang, Bingyan Zhou, Di Wang, Ke Chen, Handan Mao, Bin Wang, Jianghua Zhan, Cong-Yi Wang, Wanjiang Zeng, Feng Chen, Bo Xiong, Jiexiong Feng","doi":"10.1186/s13073-025-01538-1","DOIUrl":"10.1186/s13073-025-01538-1","url":null,"abstract":"<p><strong>Background: </strong>The enteric nervous system (ENS), which arises from enteric neural crest cells (ENCCs), plays important roles in many aspects of gastrointestinal tract function, including motility, secretions, blood flow and hormone release. Defects in ENS development could lead to a broad range of disorders, including Hirschsprung's disease (HSCR), which is characterized by missing nerve cells in the distal segment of the colon. Here, we identify EMB as an evolutionarily conserved regulator of ENS development.</p><p><strong>Methods: </strong>We first examined EMB expression in human and mouse intestines using scRNA-seq data and immunofluorescence staining. To investigate its role in ENS development, we constructed Emb-knockout zebrafish and mouse models. To explore the underlying mechanisms, we focused on ENCCs and analyzed their proliferation and migration using migration assays in explant guts and organoid cultures. Finally, we assessed rare EMB variants in a cohort of HSCR patients.</p><p><strong>Results: </strong>In zebrafish, loss of emb leads to a decrease number of enteric neurons and impaired intestinal transit ability. In mice, knockout of Emb causes HSCR-like phenotypes and defects. In vitro experiments, including explant mouse gut and organoid cultures, show that EMB is required for both the proliferation and migration of ENCCs. Mechanistically, EMB binds to and recruits the phosphatase complex PP2A to the cellular membrane to facilitate the activation of PI3K-AKT pathway, thereby promoting ENCCs development. Indeed, application of PI3K or AKT agonists partially restores the ENS developmental defects in zebrafish emb mutants. Furthermore, rare variants of EMB may potentially contribute to the pathology of HSCR in humans.</p><p><strong>Conclusions: </strong>EMB is required for ENS development by regulating the proliferation and migration of the ENCCs. Mechanistically, EMB recruits PP2A to the cell membrane, reducing cytoplasmic dephosphorylation activity and promoting the activation of the PI3K signaling pathway.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"102"},"PeriodicalIF":10.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148834","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":"MorphoITH: a framework for deconvolving intra-tumor heterogeneity using tissue morphology.","authors":"Aleksandra Weronika Nielsen, Hafez Eslami Manoochehri, Hua Zhong, Vandana Panwar, Vipul Jarmale, Jay Jasti, Mehrdad Nourani, Dinesh Rakheja, James Brugarolas, Payal Kapur, Satwik Rajaram","doi":"10.1186/s13073-025-01504-x","DOIUrl":"10.1186/s13073-025-01504-x","url":null,"abstract":"<p><strong>Background: </strong>Tumor evolution, driven by the emergence of genetically and epigenetically distinct subclones, enables cancers to adapt to selective pressures and become more aggressive, posing a major challenge in oncology. Multi-regional sequencing has been the primary means of studying tumor evolution and the resultant intra-tumor heterogeneity (ITH), but its high cost, resource-intensiveness, and limited scalability have hindered clinical utility.</p><p><strong>Methods: </strong>Here, we present MorphoITH, a novel framework that aims to infer molecular ITH from routinely collected histopathology slides by quantifying phenotypic diversity. MorphoITH integrates a task-agnostic, self-supervised deep learning similarity measure to capture phenotypic variation across multiple dimensions (cytology, architecture, and microenvironment) along with rigorous methods to eliminate spurious sources of variation.</p><p><strong>Results: </strong>Applying MorphoITH to clear cell renal cell carcinoma (ccRCC), a disease notably shaped by ITH, we show that it captures clinically significant biological features such as vascular architecture and nuclear grade. MorphoITH also recognizes morphological changes associated with subclonal alterations in key driver genes (BAP1, PBRM1, SETD2). Finally, in a multi-regional sequencing dataset, we find that the morphological trajectories revealed by MorphoITH largely mirror underlying patterns of genetic evolution.</p><p><strong>Conclusions: </strong>MorphoITH provides a scalable and rigorous approach to quantify morphological ITH, serving as a potential proxy for underlying genetic ITH and tumor evolution. By linking histopathology with genomic insights, it lays the foundation for more refined phenotypic profiling in support of precision oncology.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"101"},"PeriodicalIF":10.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12447597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085932","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":"Evaluating genome sequencing strategies: trio, singleton, and standard testing in rare disease diagnosis.","authors":"Daniel Kaschta, Christina Post, Franziska Gaass, Milad Al-Tawil, Vincent Arriens, Saranya Balachandran, Tobias Bäumer, Valerie Berge, Friederike Birgel, Andreas Dalski, Maike Dittmar, Andre Franke, Sören Franzenburg, Janina Fuß, Bettina Gehring, Rebecca Gembicki, Bianca Greiten, Kristin Grohte, Britta Hanker, Kristian Händler, Lana Harder, Yorck Hellenbroich, Theresia Herget, Gloria Herrmann, Olaf Hiort, Kirstin Hoff, Birga Hoffmann, Nadine Hornig, Irina Hüning, Monika Kautza-Lucht, Juliane Köhler, Anna-Sophie Liegmann, Jasmin Lisfeld, Britt-Sabina Löscher, Nils G Margraf, Michelle Meyenborg, Anna Möllring, Hiltrud Muhle, Eva Maria Murga Penas, Henning Nommels, Dzhoy Papingi, Imke Poggenburg, Jelena Pozojevic, Philip Rosenstiel, Andreas Recke, Kimberly Roberts, Laelia Rösler, Franka Rust, Maj-Britt Salewski, Katharina Schau-Römer, Christian Schlein, Varun K A Sreenivasan, Louiza Toutouna, Caroline Utermann-Thüsing, Amelie T van der Ven, Alexander E Volk, Janne Wehnert, Sandra Wilson, Rixa Woitschach, Veronica Yumiceba, Christine Zühlke, Alexander Münchau, Norbert Brüggemann, Inga Vater, Almuth Caliebe, Inga Nagel, Malte Spielmann","doi":"10.1186/s13073-025-01516-7","DOIUrl":"10.1186/s13073-025-01516-7","url":null,"abstract":"<p><strong>Background: </strong>Short-read genome sequencing (GS) is among the most comprehensive genetic testing methods available, capable of detecting single-nucleotide variants, copy-number variants, mitochondrial variants, repeat expansions, and structural variants in a single assay. Despite its technical advantages, the full clinical utility of GS in real-world diagnostic settings remains to be fully established.</p><p><strong>Methods: </strong>This study systematically compared singleton GS (sGS), trio GS (tGS), and exome sequencing-based standard-of-care (SoC) genetic testing in 416 patients with rare diseases in a blinded, prospective study. Three independent teams with divergent baseline expertise evaluated the diagnostic yield of GS as a unifying first-tier test and directly compared its variant detection capabilities, learning curve, and clinical feasibility. The SoC team had extensive prior experience in exome-based diagnostics, while the sGS and tGS teams were newly trained in GS interpretation. Diagnostic yield was assessed through both prospective and retrospective analyses.</p><p><strong>Results: </strong>In our prospective analysis, tGS achieved the highest diagnostic yield for likely pathogenic/pathogenic variants at 36.1% in the newly trained team, surpassing the experienced SoC team at 35.1% and the newly trained sGS team at 28.8%. To evaluate which variants could technically be identified and account for differences in team experience, we conducted a retrospective analysis, achieving diagnostic yields of 36.7% for SoC, 39.1% for sGS, and 40.0% for tGS. The superior yield of GS was attributed to its ability to detect deep intronic, non-coding, and small copy-number variants missed by SoC. Notably, tGS identified three de novo variants classified as likely pathogenic based on recent GeneMatcher collaborations and newly published gene-disease association studies.</p><p><strong>Conclusions: </strong>Our findings demonstrate that GS, particularly tGS, outperforms SoC in diagnosing rare diseases, with sGS providing a more cost-effective alternative. These results suggest that GS should be considered a first-tier genetic test, offering an efficient, single-step approach to reduce the diagnostic odyssey for patients with rare diseases. The trio approach proved especially valuable for less experienced teams, as inheritance data facilitated variant interpretation and maintained high diagnostic yield, while experienced teams achieved comparable results with singleton analysis alone.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"100"},"PeriodicalIF":10.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080347","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":"Publisher Correction: Evaluation of familial phenotype deviation to measure the impact of de novo mutations in autism.","authors":"Soo-Whee Kim, Hyeji Lee, Da Yea Song, Gang-Hee Lee, Jae Hyun Han, Jee Won Lee, Hee Jung Byun, Ji Hyun Son, Ye Rim Kim, Yoojeong Lee, Eunjoon Kim, Donna M Werling, So Hyun Kim, Stephan J Sanders, Hee Jeong Yoo, Joon-Yong An","doi":"10.1186/s13073-025-01540-7","DOIUrl":"10.1186/s13073-025-01540-7","url":null,"abstract":"","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"99"},"PeriodicalIF":10.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000411","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}