Human Genetics最新文献

{"title":"Accelerating genetic diagnostics in retinitis pigmentosa: implementation of a semi-automated bespoke cohort analysis workflow for Hong Kong Genome Project.","authors":"Dingge Ying, Jamie Sui Lam Kwok, Annie Tsz Wai Chu, Wei Ma, Helen Ying Fung Tam, Dicky Or, Shirley Pik Ying Hue, Qing Li, Christopher Kai Shun Leung, Brian Hon Yin Chung","doi":"10.1007/s00439-025-02737-x","DOIUrl":"10.1007/s00439-025-02737-x","url":null,"abstract":"<p><p>The study aims to enhance the efficiency of the genetic variant curation process at the Hong Kong Genome Institute by developing a Semi-Automated Bespoke Cohort Analysis Workflow (S-BCAW) for patients with, or suspected to have, retinitis pigmentosa (RP) in the Hong Kong Genome Project (HKGP), leveraging advances in next-generation sequencing (NGS). A comparative analysis involving 79 RP patients was conducted using both the conventional manual workflow and the novel S-BCAW, which integrates initial filtering and variant classification based on ACMG guidelines, followed by detailed manual review. The diagnostic yields from both methods were identical, but the bespoke workflow reduced analysis time by approximately 60% (1.5 h/sample). This efficiency increase resulted from automated application of ACMG rules and systematic aggregation of supportive data, including disease-specific information. The study reports 25 positive cases with a diagnostic yield of 32%, including three novel variants. The S-BCAW significantly improves efficiency, helping to end the diagnostic odyssey for patients in the HKGP. This approach facilitates rapid assessment of variant pathogenicity, enhancing the feasibility and timeliness of NGS technology for clinical applications, especially in urgent scenarios.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"515-528"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive profiling of tsRNAs in acute coronary syndrome: expression patterns, clinical correlations, and functional insights.","authors":"Yi He, Jing Wang, Chen Chen, Rongli Wang, Xiaozhu Ma, Ruiying Ma, Yang Sun, Luyun Wang, Hu Ding","doi":"10.1007/s00439-025-02742-0","DOIUrl":"https://doi.org/10.1007/s00439-025-02742-0","url":null,"abstract":"<p><p>Transfer RNA-derived small RNAs (tsRNAs) have emerged as potential biomarkers of various human diseases. However, the clinical utility and biological functions of tsRNA in acute coronary syndrome (ACS) remain poorly understood. To investigate this, we performed high-throughput small RNA sequencing on peripheral blood monocyte cells (PBMCs) from 24 ACS patients and 12 healthy controls. Our analysis revealed distinct and characteristic expression patterns of tsRNAs in response to ACS, highlighting their potential as disease signatures in human PBMCs. Differentially expressed tsRNAs were validated using RT-qPCR in two independent case-control sets. Among these, tRF-Gly-GCC-06 was significantly upregulated in volunteers with unstable angina (UA) and acute myocardial infarction (AMI) (p < 0.05) and showed a statistically significant positive correlation with the Gensini score (r = 0.353, p < 0.001). Moreover, this tsRNA was independently associated with an increased risk of ACS after adjusting for conventional cardiovascular risk factors (odds ratio (OR) = 1.58, 95% confidence interval (CI): 1.37-1.83, p < 0.001). A series of functional studies showed that tRF-Gly-GCC-06 significantly facilitated macrophage proliferation and migration and modulated inflammation-related gene expression in vitro. This study identified a novel functional gene associated with ACS, tRF-Gly-GCC-06, as a potential clinical biomarker and therapeutic target.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"575-590"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 molecular landscape of hereditary ataxia: a single-center study.","authors":"Elisa Bregant, Elena Betto, Chiara Dal Secco, Jessica Zucco, Federica Baldan, Lorenzo Allegri, Incoronata Renata Lonigro, Flavio Faletra, Lorenzo Verriello, Giuseppe Damante, Catia Mio","doi":"10.1007/s00439-025-02744-y","DOIUrl":"https://doi.org/10.1007/s00439-025-02744-y","url":null,"abstract":"<p><p>Hereditary ataxia (HA) is a heterogeneous group of complex neurological disorders, which represent a diagnostic challenge due to their diverse phenotypes and genetic etiologies. Next-generation sequencing (NGS) has revolutionized the field of neurogenetics, improving the identification of ataxia-associated genes. Notwithstanding, repeat expansions analysis remains a cornerstone in the diagnostic workflow of these diseases. Here we describe the molecular characterization of a consecutive single-center series of 70 patients with genetically uncharacterized HA. Patients' samples were analyzed for known HA-associated repeat expansions as first tier and negative ones were analyzed by whole exome sequencing (WES) as second tier. Overall, we identified pathogenic/likely pathogenic variants in 40% (n = 28/70) and variants of unknown significance (VUS) in 20% (n = 14/70) of cases. In particular, 10 patients (14.3%, n = 10/70) presented pathogenic repeat expansions while 18 cases (30%, n = 18/60) harbored at least a single nucleotide variant (SNV) or a copy number variant (CNV) in HA or HSP-related genes. WES allowed assessing complex neurological diseases (i.e., leukodystrophies, cerebrotendinous xanthomatosis and atypical xeroderma pigmentosum), which are not usually referred as pure genetic ataxias. Our data suggests that the combined use of repeat expansion analysis and WES, coupled to detailed clinical phenotyping, is able to detect the molecular alteration underpinning ataxia in almost 50% cases, regardless of the hereditary pattern. Indeed, NGS-based tests are fundamental to acknowledge novel HA-associated genes useful to explain the remaining wide fraction of negative tests. Nowadays, this gap is problematic since these patients could not benefit from an etiological diagnosis of their disease that allows prognostic trajectories and prenatal/preimplantation diagnosis.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"545-557"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor.","authors":"Wouter H van der Valk, Winnie M C van den Boogaard, Esther Fousert, Heiko Locher","doi":"10.1007/s00439-025-02741-1","DOIUrl":"10.1007/s00439-025-02741-1","url":null,"abstract":"","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"591-593"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Congenital enteropathy caused by ezrin deficiency.","authors":"Georg F Vogel, Katharina M C Klee, Arzu Meltem Demir, Dorota Garczarczyk-Asim, Michael W Hess, Lukas A Huber, Thomas Müller, Andreas R Janecke","doi":"10.1007/s00439-025-02738-w","DOIUrl":"10.1007/s00439-025-02738-w","url":null,"abstract":"<p><p>Ezrin, encoded by EZR, is a central module of epithelial polarity and links membrane proteins to the actin cytoskeleton directly or indirectly through scaffold proteins in the epithelium. Ezrin knockout mice fail to thrive and do not survive past weaning. We identified a homozygous EZR loss-of-function (LoF) variant, c.356dup, by exome sequencing in an infant with intractable diarrhea and failure to thrive, who died from septicemia at 5 months of age. The variant localized within a homozygous region of 13.2 Mb in the proband, is consistent with inheritance identical-by-descent from the consanguineous parents, and segregated with disease in the proband's family. EZR transcript analyses in a heterozygous carrier showed that the variant triggers nonsense-mediated mRNA decay. Homozygous EZR LoF variants have not been reported in public databases. In this study, we generated a Caco-2 EZR knockout cell line to investigate the role of ezrin in human intestinal epithelia. Our analyses used electron and immunofluorescence microscopy to assess structural changes in the knockout cells. We observed significant disorganization of the terminal web region, microvillus rarefaction and abnormal branching. Furthermore, the absence of ezrin resulted in the mislocalization of the ezrin-interacting scaffold protein Na+/H + exchanger regulatory factor-1. In conclusion, this represents the first documentation of complete ezrin deficiency in humans, highlighting the essential and non-redundant functions of the protein in maintaining intestinal physiology.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"505-514"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 latent outcome variable approach for Mendelian randomization using the stochastic expectation maximization algorithm.","authors":"Lamessa Dube Amente, Natalie T Mills, Thuc Duy Le, Elina Hyppönen, S Hong Lee","doi":"10.1007/s00439-025-02739-9","DOIUrl":"https://doi.org/10.1007/s00439-025-02739-9","url":null,"abstract":"<p><p>Mendelian randomization (MR) is a widely used tool to uncover causal relationships between exposures and outcomes. However, existing MR methods can suffer from inflated type I error rates and biased causal effects in the presence of invalid instruments. Our proposed method enhances MR analysis by augmenting latent phenotypes of the outcome, explicitly disentangling horizontal and vertical pleiotropy effects. This allows for explicit assessment of the exclusion restriction assumption and iteratively refines causal estimates through the expectation-maximization algorithm. This approach offers a unique and potentially more precise framework compared to existing MR methods. We rigorously evaluate our method against established MR approaches across diverse simulation scenarios, including balanced and directional pleiotropy, as well as violations of the Instrument Strength Independent of Direct Effect (InSIDE) assumption. Our findings consistently demonstrate superior performance of our method in terms of controlling type I error rates, bias, and robustness to genetic confounding, regardless of whether individual-level or summary data is used. Additionally, our method facilitates testing for directional horizontal pleiotropy and outperforms MR-Egger in this regard, while also effectively testing for violations of the InSIDE assumption. We apply our method to real data, demonstrating its effectiveness compared to traditional MR methods. This analysis reveals the causal effects of body mass index (BMI) on metabolic syndrome (MetS) and a composite MetS score calculated by the weighted sum of its component factors. While the causal relationship is consistent across most methods, our proposed method shows fewer violations of the exclusion restriction assumption, especially for MetS scores where horizontal pleiotropy persists and other methods suffer from inflation.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"559-574"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing chronic myeloid leukemia research with next-generation sequencing: potential benefits, limitations, and future clinical integration.","authors":"Henry Sutanto, Laras Pratiwi, Pradana Zaky Romadhon, Siprianus Ugroseno Yudho Bintoro","doi":"10.1007/s00439-025-02745-x","DOIUrl":"https://doi.org/10.1007/s00439-025-02745-x","url":null,"abstract":"<p><p>Next-generation sequencing (NGS) has emerged as a powerful tool for advancing research in chronic myeloid leukemia (CML) by providing a deeper understanding of its genetic complexity. Beyond detecting the hallmark BCR::ABL1 fusion gene, NGS has enabled the identification of additional mutations associated with disease progression, therapy resistance, and clonal evolution. NGS also facilitates the detection of rare BCR::ABL1 fusion variants and cryptic rearrangements, offering a more refined genetic characterization of the disease. Additionally, it enhances the study of minimal residual disease (MRD) and evolving resistance patterns, which are crucial for developing targeted therapeutic strategies. However, challenges such as data interpretation, standardization, and cost constraints continue to limit the widespread application of NGS in routine research and clinical settings. This review explores the contributions of NGS to CML research, highlighting its role in uncovering novel genetic alterations, tracking clonal evolution, and identifying potential therapeutic targets. As sequencing technologies evolve, NGS is expected to further shape the future of CML research, providing critical insights that may ultimately refine disease management strategies.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"481-503"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secondary findings in hereditary cancer genes after germline genetic testing - systematic review of literature.","authors":"Eva Avsec, Ana Blatnik, Mateja Krajc","doi":"10.1007/s00439-025-02746-w","DOIUrl":"https://doi.org/10.1007/s00439-025-02746-w","url":null,"abstract":"<p><p>In the last decade the increasing use of germline genetic testing has led to frequent discoveries of secondary findings (SF) in hereditary cancer (HC) genes. Disclosure and clinical management of such findings are still not clearly defined and raise many ethical, clinical, and practical questions. This systematic review is focused on frequency of reported SF in HC genes across different populations as well as summarizing current guidelines, recommendations, and actual clinical practice about reporting and managing SF in HC genes. A systematic literature search according to the PRISMA guidelines was performed on the electronic database PubMed from inception to June 2024. 30 research papers involving almost 150,000 patients were reviewed. The reported frequencies of SF in HC genes varied between 0.4 and 3.1%. The majority of patients agreed to receive SF for medically actionable genes. Management and surveillance of patients after disclosure of SF in HC genes were rarely reported, but the limited data show no regret of receiving such results as well as diagnoses of early-stage cancer in patients participating in recommended surveillance programs related to SF. A substantial number of carriers of highly penetrant pathogenic variants in HC genes is discovered by reporting SF after germline genetic testing with next-generation sequencing. Additional information about the impact of SF disclosure on individuals and health care systems is needed to optimize the integration of SF into clinical care.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing genotype and phenotype data for population-scale variant classification using large language models and bayesian inference.","authors":"Toby R Manders, Christopher A Tan, Yuya Kobayashi, Alexander Wahl, Carlos Araya, Alexandre Colavin, Flavia M Facio, Hillery Metz, Jason Reuter, Laure Frésard, Samskruthi R Padigepati, David A Stafford, Robert L Nussbaum, Keith Nykamp","doi":"10.1007/s00439-025-02743-z","DOIUrl":"https://doi.org/10.1007/s00439-025-02743-z","url":null,"abstract":"<p><p>Variants of Uncertain Significance (VUS) in genetic testing for hereditary diseases burden patients and clinicians, yet clinical data that could reduce VUS are underutilized due to a lack of scalable strategies. We assessed whether a machine learning approach using genotype and phenotype data could improve variant classification and reduce VUS. In this cohort study of a multi-step machine learning approach, patient data from test requisition forms were used to distinguish patients with molecular diagnoses from controls (\"patient score\"). A generative Bayesian model then used patient scores and variant classifications to infer variant pathogenicity (\"variant score\"). The study included 3.5 million patients referred for clinical genetic testing across various conditions. Primary outcomes were model- and gene-level discrimination, classification performance, probabilistic calibration, and concordance with orthogonal pathogenicity measures. Integration into a semi-quantitative classification framework was based on posterior pathogenicity probabilities matching PPV ≥ 0.99/NPV ≥ 0.95 thresholds, followed by expert review. We generated 1,334 clinical variant models (CVMs); 595 showed high performance in both machine learning steps (AUROCpatient ≥ 0.8 and AUROCvariant ≥ 0.8) on held-out data. High-confidence predictions from these CVMs provided evidence for 5,362 VUS observed in 200,174 patients, representing 23.4% of all VUS observations in these genes. In 17 frequently tested genes, CVMs reclassified over 1,000 unique VUS, reducing VUS report rates by 9-49% per condition. In conclusion, a scalable machine learning approach using underutilized clinical data improved variant classification and reduced VUS.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decade-long application of preimplantation genetic testing for DMD/BMD: analysis of five clinical strategies and embryo recombination patterns.","authors":"Weili Wang, Jing Dai, Xiao Hu, Wenbin He, Yifan Gu, Zhenxing Wan, Yi Zhang, Keli Luo, Wen Li, Qianjun Zhang, Fei Gong, Guangxiu Lu, Liang Hu, Yue-Qiu Tan, Ge Lin, Juan Du","doi":"10.1007/s00439-025-02728-y","DOIUrl":"10.1007/s00439-025-02728-y","url":null,"abstract":"<p><p>This study aimed to find the most effective PGT-M strategy for Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD), and to reduce misdiagnosis caused by embryo recombination in DMD. A retrospective study was performed by analyzing 158 PGT-M cycles for DMD/BMD in Reproductive and Genetic Hospital of CITIC-Xiangya between 2009 and 2023. Patients' backgrounds were collected. The effectiveness and safety for five different PGT-M strategies (1-5), including mutation testing from cleavage or trophoblast ectoderm (TE) cells and additional linkage analysis post-TE cell amplification, were analyzed. The embryonic recombination events were assessed for these cycles. Mutation analysis showed that 62.4% of the 125 families had DMD deletions, 16.0% had duplications, and 21.6% had single nucleotide variants (SNVs). Among 125 families, 104 (83.2%) had previously affected fetus or offspring. The highest diagnosis rate (99.56%) was achieved with Strategy 5, which combined mutation testing with SNP-based linkage analysis in TE cells. This strategy 5 also demonstrated an advantage in cases with recombination near the mutation. An intragenic recombination rate of 5.5% was observed in embryos, predominantly in the hotspots (exons 45-55 and exons 3-9) of DMD deletion/duplication mutations. Prenatal diagnosis for 52 families and successful outcomes in all 85 healthy deliveries (live birth rate, 65.89%, 85/129) validated the accuracy and effectiveness of PGT-M. This study provides a highly effective PGT-M strategy (Strategy 5) for DMD/BMD by comparing five different strategies, with the diagnostic yield reaching 99.56%. The results underscore the significance of monitoring intragenic recombination in DMD, which is a frequent occurrence in DMD/BMD.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"405-416"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}