Genome Medicine最新文献

{"title":"DNA repair and the contribution to chemotherapy resistance.","authors":"Ksenija Nesic, Phoebe Parker, Elizabeth M Swisher, John J Krais","doi":"10.1186/s13073-025-01488-8","DOIUrl":"10.1186/s13073-025-01488-8","url":null,"abstract":"<p><p>The DNA damage response comprises a set of imperfect pathways that maintain cell survival following exposure to DNA damaging agents. Cancers frequently exhibit DNA repair pathway alterations that contribute to their intrinsic genome instability. This, in part, facilitates a therapeutic window for many chemotherapeutic agents whose mechanisms of action often converge at the generation of a double-strand DNA break. The development of therapy resistance occurs through countless molecular mechanisms that promote tolerance to DNA damage, often by preventing break formation or increasing repair capacity. This review broadly discusses the DNA damaging mechanisms of action for different classes of chemotherapeutics, how avoidance and repair of double-strand breaks can promote resistance, and strategic directions for counteracting therapy resistance.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"62"},"PeriodicalIF":10.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The case for including proteomics in routine diagnostic practice for rare disease.","authors":"Elizabeth M McCormick","doi":"10.1186/s13073-025-01491-z","DOIUrl":"10.1186/s13073-025-01491-z","url":null,"abstract":"<p><p>Many people with rare diseases cannot access personalized therapies because they do not have a confirmed genetic diagnosis. Promising technologies including proteomics are underutilized in routine diagnostic practice. It is time to incorporate proteomics into the diagnostic workflow to shorten time to diagnosis and expand treatment options for rare disease.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"61"},"PeriodicalIF":10.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150183","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":"Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases.","authors":"Daniella H Hock, Nikeisha J Caruana, Liana N Semcesen, Nicole J Lake, Luke E Formosa, Sumudu S C Amarasekera, Tegan Stait, Simone Tregoning, Leah E Frajman, Adam M Bournazos, David R L Robinson, Megan Ball, Boris Reljic, Bryony Ryder, Mathew J Wallis, Anand Vasudevan, Cara Beck, Heidi Peters, Joy Lee, Natalie B Tan, Mary-Louise Freckmann, Vasiliki Karlaftis, Chantal Attard, Paul Monagle, Amanda Samarasinghe, Rosie Brown, Weimin Bi, Monkol Lek, Robert McFarland, Robert W Taylor, Michael T Ryan, Sandra T Cooper, Zornitza Stark, John Christodoulou, Alison G Compton, David R Thorburn, David A Stroud","doi":"10.1186/s13073-025-01467-z","DOIUrl":"10.1186/s13073-025-01467-z","url":null,"abstract":"<p><strong>Background: </strong>Only half of individuals with suspected rare diseases receive a genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate care, restores reproductive confidence and reduces the number of potentially unnecessary interventions. A major barrier is the lack of disease agnostic functional tests suitable for implementation in routine diagnostics that can provide evidence supporting pathogenicity of novel variants, especially those refractory to RNA sequencing.</p><p><strong>Methods: </strong>Focusing on mitochondrial disease, we describe an untargeted mass-spectrometry based proteomics pipeline that can quantify proteins encoded by > 50% of Mendelian disease genes and > 80% of known mitochondrial disease genes in clinically relevant sample types, including peripheral blood mononuclear cells (PBMCs). In total we profiled > 90 individuals including undiagnosed individuals suspected of mitochondrial disease and a supporting cohort of disease controls harbouring pathogenic variants in nuclear and mitochondrial genes. Proteomics data were benchmarked against pathology accredited respiratory chain enzymology to assess the performance of proteomics as a functional test. Proteomics testing was subsequently applied to individuals with suspected mitochondrial disease, including a critically ill infant with a view toward rapid interpretation of variants identified in ultra-rapid genome sequencing.</p><p><strong>Results: </strong>Proteomics testing provided evidence to support variant pathogenicity in 83% of individuals in a cohort with confirmed mitochondrial disease, outperforming clinical respiratory chain enzymology. Freely available bioinformatic tools and criteria developed for this study ( https://rdms.app/ ) allow mitochondrial dysfunction to be identified in proteomics data with high confidence. Application of proteomics to undiagnosed individuals led to 6 additional diagnoses, including a mitochondrial phenocopy disorder, highlighting the disease agnostic nature of proteomics. Use of PBMCs as a sample type allowed rapid return of proteomics data supporting pathogenicity of novel variants identified through ultra-rapid genome sequencing in as little as 54 h.</p><p><strong>Conclusions: </strong>This study provides a framework to support the integration of a single untargeted proteomics test into routine diagnostic practice for the diagnosis of mitochondrial and potentially other rare genetic disorders in clinically actionable timelines, offering a paradigm shift for the functional validation of genetic variants.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"58"},"PeriodicalIF":10.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119583","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":"Systematic analysis of genetic and phenotypic characteristics reveals antisense oligonucleotide therapy potential for one-third of neurodevelopmental disorders.","authors":"Kim N Wijnant, Nael Nadif Kasri, Lisenka E L M Vissers","doi":"10.1186/s13073-025-01477-x","DOIUrl":"10.1186/s13073-025-01477-x","url":null,"abstract":"<p><strong>Background: </strong>Neurodevelopmental disorders (NDDs) are a challenging group of disorders to treat, but promising therapeutic interventions in the form of antisense oligonucleotides (AONs) have emerged in recent years. However, the applicability of AON therapy for NDDs varies based on genetic and phenotypic traits. In this study we systematically evaluated key characteristics for AON therapy suitability in NDDs, to estimate overall therapy potential and identify, both well- and less-studied, targetable NDDs.</p><p><strong>Methods: </strong>An NDD dataset was created and evaluated to identify potentially targetable NDDs for seven AON strategies. This involved examining the presence of a combination of critical factors including disease-gene properties, such as regulatory elements, effects of pathogenic variants, and disease-associated phenotypic features.</p><p><strong>Results: </strong>Through the systematic evaluation of the presence of targetable characteristic for each NDD and AON strategy, we identified 711 NDDs (38% of the total) with characteristics favorable for at least one AON strategy and predicted that 18% of affected individuals could benefit from AON therapy.</p><p><strong>Conclusions: </strong>The results from our analysis demonstrate that there might be a more extensive potential for the use of AON therapy in NDDs than was anticipated thus far, underscoring AON therapy as a promising treatment option for NDDs while simultaneously contributing to informed therapy selection.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"59"},"PeriodicalIF":10.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119582","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":"Enhancing infectious intestinal disease diagnosis through metagenomic and metatranscriptomic sequencing of 1000 human diarrhoeal samples.","authors":"Edward Cunningham-Oakes, Blanca M Perez-Sepulveda, Yan Li, Jay C D Hinton, Charlotte A Nelson, K Marie McIntyre, Maya Wardeh, Sam Haldenby, Richard Gregory, Miren Iturriza-Gómara, Christiane Hertz-Fowler, Sarah J O'Brien, Nigel A Cunliffe, Alistair C Darby","doi":"10.1186/s13073-025-01478-w","DOIUrl":"https://doi.org/10.1186/s13073-025-01478-w","url":null,"abstract":"<p><strong>Background: </strong>Current surveillance of diarrhoeal disease is hindered by limitations of traditional diagnostic approaches, which often fail to identify the causative organism, particularly for novel or hard-to-culture bacterial pathogens. Sequencing nucleic acids directly from stool can overcome such constraints, but such approaches need to reliably detect pathogens identifiable by conventional methods.</p><p><strong>Methods: </strong>As part of the INTEGRATE study, we analysed stool microbiomes from 1067 patients with gastroenteritis symptoms using direct sequencing, and compared findings with standard diagnostic techniques (culture, immunoassay, microscopy, and single-target PCR) and molecular assays (Luminex xTAG GPP) for detection of bacterial and viral pathogens in the UK.</p><p><strong>Results: </strong>We found strong positive correlations between metatranscriptomic reads and traditional diagnostics for six out of 15 pathogens. The metatranscriptomic data were highly correlated with the Luminex assay for eight out of 14 pathogens. In contrast, metagenomic sequencing only showed a strong positive correlation with traditional diagnostics for three of 15 pathogens, and with Luminex for four of 14 pathogens. Compared with metagenomics, metatranscriptomics had increased sensitivity of detection for four pathogens, while metagenomics was more effective for detecting five pathogens. Metatranscriptomics gave near-complete transcriptome coverage for Human mastadenovirus F and detected Cryptosporidium via identification of Cryptosporidium parvum virus (CSpV1). A comprehensive transcriptomic profile of Salmonella enterica serovar Enteritidis was recovered from the stool of a patient with a laboratory-confirmed Salmonella infection. Furthermore, comparison of RNA/DNA ratios between pathogen-positive and pathogen-negative samples demonstrated that metatranscriptomics can distinguish pathogen-positive/negative samples and provide insights into pathogen biology. Higher RNA/DNA ratios were observed in samples that tested positive via gold-standard diagnostics.</p><p><strong>Conclusions: </strong>This study highlights the power of directly sequencing nucleic acids from human samples to augment gastrointestinal pathogen surveillance and clinical diagnostics. Metatranscriptomics was most effective for identifying a wide range of pathogens and showed superior sensitivity. We propose that metatranscriptomics should be considered for future diagnosis and surveillance of gastrointestinal pathogens. We assembled a rich data resource of paired metagenomic and metatranscriptomic datasets, direct from patient stool samples, and have made these data publicly available to enhance the understanding of pathogens associated with infectious intestinal diseases.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"55"},"PeriodicalIF":10.4,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208403","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":"Spatiotemporal single-cell analysis elucidates the cellular and molecular dynamics of human cornea aging.","authors":"Dan Jiang, Ke Li, Yining Sun, Zicheng Zhang, Shuang Xie, Xintong Yu, Ruoqi Wang, Ying Feng, Qinxiang Zheng, Yajing Wen, Peter S Reinach, Yuanyuan Du, Meng Zhou, Wei Chen","doi":"10.1186/s13073-025-01475-z","DOIUrl":"10.1186/s13073-025-01475-z","url":null,"abstract":"<p><strong>Background: </strong>The human cornea is a transparent and uniquely ordered optical-biological system. Precise coordination of its cellular mechanisms is essential to maintain its transparency and functionality. However, the spatial, cellular and molecular architecture of the human cornea and its intercellular interactions during aging have not been elucidated.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing (scRNA-seq) and single-cell SpaTial Enhanced REsolution Omics-sequencing (scStereo-seq) analysis in corneal tissue from eight eyes of donors aged 33-88 years to elucidate the spatiotemporal cellular and molecular dynamics of human cornea aging. Immunofluorescence staining and Western blotting were performed to validate the findings.</p><p><strong>Results: </strong>Spatiotemporal single-cell analysis revealed the complex cellular landscape, spatial organization and intercellular communication within the human cornea. The subpopulations of major cell types of the cornea were elucidated with precise spatial positions. In particular, we identified novel subpopulations, mapped the spatial positioning of limbal stem cells within the limbal niche, and delineated the interactions between major cell types. We observed that three basal cell subsets migrate centripetally from the peripheral to the central cornea with age, suggesting the \"spatiotemporal centripetal pattern\" as a novel paradigm for the age-related migration of corneal epithelial cells. Furthermore, we elucidated the age-related, region-specific molecular and functional characteristics of the corneal endothelium, demonstrating differential metabolic capacities and functional properties between the peripheral and central regions.</p><p><strong>Conclusions: </strong>As the first comprehensive spatiotemporal atlas, our work provides a valuable resource for understanding tissue homeostasis in the human cornea and advances research on corneal pathology, transplantation, senescence and regenerative medicine in the context of corneal aging.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"56"},"PeriodicalIF":10.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101752","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":"RNA polymerase I is essential for driving the formation of 3D genome in early embryonic development in mouse, but not in human.","authors":"Changliang Hou, Geng G Tian, Shuanggang Hu, Beili Chen, Xiaoyong Li, Bo Xu, Yuedi Cao, Wei Le, Rong Hu, Hao Chen, Yan Zhang, Qian Fang, Man Zhang, Zhaoxia Wang, Zhiguo Zhang, Jinfu Zhang, Zhaolian Wei, Guangxin Yao, Yefan Wang, Ping Yin, Ya Guo, Guoqing Tong, Xiaoming Teng, Yun Sun, Yunxia Cao, Ji Wu","doi":"10.1186/s13073-025-01476-y","DOIUrl":"10.1186/s13073-025-01476-y","url":null,"abstract":"<p><strong>Background: </strong>Three-dimensional (3D) chromatin architecture undergoes dynamic reorganization during mammalian gametogenesis and early embryogenesis. While mouse studies have shown species-specific patterns as well as mechanisms underlying de novo organization, these remain poorly characterized in humans. Although RNA polymerases II and III have been shown to regulate chromatin structure, the potential role of RNA polymerase I (Pol I), which drives ribosomal RNA production, in shaping 3D genome organization during these developmental transitions has not been investigated.</p><p><strong>Methods: </strong>We employed a modified low-input in situ Hi-C approach to systematically compare 3D genome architecture dynamics from gametogenesis through early embryogenesis in human and mouse. Complementary Smart-seq2 for low-input transcriptomics, CUT&Tag for Pol I profiling, and Pol I functional inhibition assays were performed to elucidate the mechanisms governing chromatin organization.</p><p><strong>Results: </strong>Our study revealed an extensive reorganization of the 3D genome from human oogenesis to early embryogenesis, displaying significant differences with the mouse, including dramatically attenuated topologically associating domains (TADs) at germinal vesicle (GV) stage oocytes. The 3D genome reconstruction timing is a fundamental difference between species. In human, reconstruction initiates at the 4-cell stage embryo in human, while in mouse, it commences at the 2-cell stage embryo. We discovered that Pol I is crucial for establishing the chromatin structures during mouse embryogenesis, but not in human embryos. Intriguingly, the absence of Pol I transcription weakens TAD structure in mouse female germline stem cells, whereas it fortifies it in human counterparts.</p><p><strong>Conclusions: </strong>These observed interspecies distinctions in chromatin organization dynamics provide novel insights into the evolutionary divergence of chromatin architecture regulation during early mammalian development. Our findings provide mechanistic insights into species-specific chromatin organization during germ cell and embryonic development and have potential implications for fertility preservation and birth defect prevention.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"57"},"PeriodicalIF":10.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101740","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 pathway-based effects of blood pressure and body mass index on cardiovascular traits: comparison of novel Mendelian randomization approaches.","authors":"Genevieve M Leyden, Maria K Sobczyk, Tom G Richardson, Tom R Gaunt","doi":"10.1186/s13073-025-01472-2","DOIUrl":"10.1186/s13073-025-01472-2","url":null,"abstract":"<p><strong>Background: </strong>Mendelian randomization (MR) leverages trait associated genetic variants as instrumental variables (IVs) to determine causal relationships in epidemiology. However, genetic IVs for complex traits are typically highly heterogeneous and, at a molecular level, exert effects on different biological processes. Exploration of the biological underpinnings of such heterogeneity can enhance our understanding of disease mechanisms and inform therapeutic strategies. Here, we introduce a new approach to instrument partitioning based on enrichment of Mendelian disease categories (pathway-partitioned) and compare it to an existing method based on genetic colocalization in contrasting tissues (tissue-partitioned).</p><p><strong>Methods: </strong>We employed individual- and summary-level MR methodologies using SNPs grouped by pathway informed by proximity to Mendelian disease genes affecting the renal system or vasculature (for blood pressure (BP)), or mental health and metabolic disorders (for body mass index (BMI)). We compared the causal effects of pathway-partitioned SNPs on cardiometabolic outcomes with those derived using tissue-partitioned SNPs informed by colocalization with gene expression in kidney, artery (BP), or adipose and brain tissues (BMI). Additionally, we assessed the likelihood that estimates observed for partitioned exposures could emerge by chance using random SNP sampling.</p><p><strong>Results: </strong>Our pathway-partitioned findings suggest the causal relationship between systolic BP and heart disease is predominantly driven by vessel over renal pathways. The stronger effect attributed to kidney over artery tissue in our tissue-partitioned MR hints at a multifaceted interplay between pathways in the disease aetiology. We consistently identified a dominant role for vessel (pathway) and artery (tissue) driving the negative directional effect of diastolic BP on left ventricular stroke volume and positive directional effect of systolic BP on type 2 diabetes. We also found when dissecting the BMI pathway contribution to atrial fibrillation that metabolic-pathway and brain-tissue IVs predominantly drove the causal effects relative to mental health and adipose in pathway- and tissue-partitioned MR analyses, respectively.</p><p><strong>Conclusions: </strong>This study presents a novel approach to dissecting heterogeneity in MR by integrating clinical phenotypes associated with Mendelian disease. Our findings emphasize the importance of understanding pathway-/tissue-specific contributions to complex exposures when interpreting causal relationships in MR. Importantly, we advocate caution and robust validation when interpreting pathway-partitioned effect size differences.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"54"},"PeriodicalIF":10.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077419","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":"Patient rights in precision oncology: right treatment, right time, right dose, right order, right place.","authors":"Elena Fountzilas, Apostolia-Maria Tsimberidou, Razelle Kurzrock","doi":"10.1186/s13073-025-01468-y","DOIUrl":"10.1186/s13073-025-01468-y","url":null,"abstract":"<p><p>Precision oncology has facilitated a transition from a one-size-fits-all to a precise individualized approach. This Comment discusses the broader challenges in the implementation of personalized treatments to further improve patients' outcomes, towards comprehensive strategies that address tumor complexity and patients' molecular portfolios, as well as quality of life and diversity considerations.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"53"},"PeriodicalIF":10.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013270","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":"Effect of newborn genomic screening for lysosomal storage disorders: a cohort study in China.","authors":"Xin Wang, Yun Sun, Xian-Wei Guan, Yan-Yun Wang, Dong-Yang Hong, Zhi-Lei Zhang, Ya-Hong Li, Pei-Ying Yang, Tao Jiang, Zheng-Feng Xu","doi":"10.1186/s13073-025-01483-z","DOIUrl":"10.1186/s13073-025-01483-z","url":null,"abstract":"<p><strong>Background: </strong>Lysosomal storage disorders (LSDs) have a relatively high incidence among rare diseases and can lead to severe consequences if not treated promptly. However, many countries and regions have not included these disorders in their newborn screening programs, resulting in missed early detection, underdiagnosis, and delayed treatment. Newborn genomic screening (NBGS) has shown good screening effectiveness for traditional biochemical screening diseases; however, its effectiveness for LSDs has not yet been evaluated in the general newborn population.</p><p><strong>Methods: </strong>To evaluate the outcome of NBGS for LSDs, a cohort study was conducted involving newborns recruited from Nanjing Women and Children's Healthcare Hospital in China from March 18, 2022, to September 21, 2023. All participants underwent NBGS of 15 LSDs (18 genes) via dried blood spots, followed by enzyme activity testing for NBGS-positive individuals. The study calculated the incidence and carrier rates for each LSD though NBGS, as well as the positive screening rate, the false positive rate and the positive predictive value of the screening process.</p><p><strong>Results: </strong>Among 22,687 newborns (11,996 males [52.88%]), 1344 (6.0%) were identified as carriers, and 30 (0.13%) were initially positive for LSDs. Of these, 4 were excluded, 15 were diagnosed as LSD-presymptomatic individuals based on enzyme deficiency and pathogenic variants conforming to inheritance patterns, and 11 remain under follow-up. The estimated combined birth incidence of LSDs in Nanjing was 1/1512, primarily including Fabry disease, Krabbe disease, glycogen storage disease type II, Niemann-Pick disease, and mucopolysaccharidosis type II. Rather than directly comparing NBGS and enzyme activity screening, this study evaluated two sequential screening strategies: (1) NBGS-first with reflex enzyme testing and (2) enzyme activity-first with reflex genomic testing. The NBGS-first strategy demonstrated higher sensitivity and specificity, with a significantly lower false positive rate and higher positive predictive values compared to the enzyme-first strategy (P < 0.05).</p><p><strong>Conclusions: </strong>This study highlights the potential of NBGS to enhance early detection of presymptomatic LSD individuals, enabling timely interventions and improving newborn health outcomes. Integrating NBGS into routine newborn screening programs could provide an effective and proactive approach for LSD identification and management.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"52"},"PeriodicalIF":10.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991727","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}