Human Genetics最新文献

Efficacy of delandistrogene moxeparvovec on Duchenne muscular dystrophy: a systematic review and meta-analysis. 德兰德消霉素莫西帕沃韦克治疗杜氏肌营养不良的疗效：系统回顾和荟萃分析。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-26 DOI: 10.1007/s00439-025-02758-6

Carlos Pascual-Morena, Silvana Patiño-Cardona, Irene Martínez-García, Jaime Fernández-Bravo-Rodrigo, Miriam Garrido-Miguel

引用次数: 0

Unraveling potential reporting bias in Mendelian randomization studies. 揭示孟德尔随机化研究中潜在的报告偏倚。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-25 DOI: 10.1007/s00439-025-02759-5

Chenyu Zhao, Keqiang Ma

引用次数: 0

Current perspectives on gene therapy and its involvement in curing genetic disorders. 基因治疗及其在遗传性疾病治疗中的作用。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-18 DOI: 10.1007/s00439-025-02757-7

Shireen Nishad, Dipali Dongare, Sayani Saha, Raskar Dhanashri Anil, Nidhi Srivastava, Abhishek Dey

{"title":"Current perspectives on gene therapy and its involvement in curing genetic disorders.","authors":"Shireen Nishad, Dipali Dongare, Sayani Saha, Raskar Dhanashri Anil, Nidhi Srivastava, Abhishek Dey","doi":"10.1007/s00439-025-02757-7","DOIUrl":"https://doi.org/10.1007/s00439-025-02757-7","url":null,"abstract":"Genomics is revolutionizing medical science, offering transformative potential for the future of medicine. Advances in whole-genome sequencing have deepened our understanding of genome structure and function, paving the way for genomic medicine. The Human Genome Project has been instrumental in identifying genetic variations linked to increased disease risks, such as cancer, enabling genome-based diagnostics and personalized therapeutic strategies. Human genomics research focuses on developing precise therapies to enhance public health and address rare genetic disorders, including Spinal muscular atrophy, Duchenne muscular dystrophy, Parkinson's disease, and Huntington's disease. Cutting-edge gene-editing tools like CRISPR allow precise and targeted modifications with minimal side effects, improving treatment efficacy. By examining the interplay of genetic factors in health and disease, genomics lays the foundation for personalized medicine. This review highlights the impact of genomics on public health and its potential to reshape healthcare through innovative treatment strategies.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325532","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}

引用次数: 0

Integrating gene mutation spectra from tumors and the general population with gene expression topological networks to identify novel cancer driver genes. 整合来自肿瘤和普通人群的基因突变谱与基因表达拓扑网络，以识别新的癌症驱动基因。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-14 DOI: 10.1007/s00439-025-02755-9

Shuangyu Yang, Dan He, Ling Li, Zhiya Lu, Shaoying Li, Tianjun Lan, Feiyi Liu, Huasong Zhang, David N Cooper, Huiying Zhao

{"title":"Integrating gene mutation spectra from tumors and the general population with gene expression topological networks to identify novel cancer driver genes.","authors":"Shuangyu Yang, Dan He, Ling Li, Zhiya Lu, Shaoying Li, Tianjun Lan, Feiyi Liu, Huasong Zhang, David N Cooper, Huiying Zhao","doi":"10.1007/s00439-025-02755-9","DOIUrl":"https://doi.org/10.1007/s00439-025-02755-9","url":null,"abstract":"Discovering cancer driver genes is critical for improving survival rates. Current methods often overlook the varying functional impacts of mutations. It is necessary to develop a method integrating mutation pathogenicity and gene expression data, enhancing the identification of novel cancer drivers. To predict cancer drivers, we have developed a framework (DGAT-cancer) that integrates the pathogenicity of somatic mutation in tumors and germline variants in the healthy population, with topological networks of gene expression in tumors, and the gene expressions in tumor and paracancerous tissues. This integration overcomes the limitations of current methods that assume a uniform impact of all mutations by leveraging a comprehensive view of mutation function within its biological context. These features were filtered by an unsupervised approach, Laplacian selection, and combined by Hotelling and Box-Cox transformations to score genes. By using gene scores as weights, Gibbs sampling was performed to identify cancer drivers. DGAT-cancer was applied to seven types of cancer cohorts, and achieved the best area under the precision-recall curve (AUPRC ranging from 0.646 to 0.862) compared to five commonly used methods (AUPRC ranging from 0.357 to 0.629). DGAT-cancer has identified 505 cancer drivers. Knockdown of the top ranked gene, EEF1A1 indicated a ~ 41-50% decrease in glioma size and improved the temozolomide sensitivity of glioma cells. By combining heterogeneous genomics and transcriptomics data, DGAT-cancer has significantly improved our ability to detect novel cancer drivers, and is an innovative approach revealing cancer therapeutic targets, thereby advancing the development of more precise and effective cancer treatments.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293673","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}

引用次数: 0

Expanding the phenotypic spectrum of PROK2/PROKR2: a recall-by-genotype study. 扩大PROK2/PROKR2表型谱：一项基于基因型的回忆研究

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-11 DOI: 10.1007/s00439-025-02754-w

Maria I Stamou, Crystal J Chiu, Shreya V Jadhav, Kathryn B Salnikov, Lacey Plummer, Stephanie B Seminara, Ravikumar Balasubramanian

{"title":"Expanding the phenotypic spectrum of PROK2/PROKR2: a recall-by-genotype study.","authors":"Maria I Stamou, Crystal J Chiu, Shreya V Jadhav, Kathryn B Salnikov, Lacey Plummer, Stephanie B Seminara, Ravikumar Balasubramanian","doi":"10.1007/s00439-025-02754-w","DOIUrl":"https://doi.org/10.1007/s00439-025-02754-w","url":null,"abstract":"Rare variants in prokineticin 2 pathway genes (PROK2; PROKR2), cause isolated hypogonadotropic hypogonadism (IHH) in humans, leading to pubertal failure and infertility. In addition to reproduction, this pathway is also implicated in cardiovascular, metabolic, and inflammatory regulation. The role of naturally occurring PROK2/R2 variants in the general population remains unknown. Thus, we aimed to investigate the role of PROK2/R2 variants in the overall human health. We performed a recall-by-genotype study in rare PROK2/R2 variant carriers and non-carrier controls from a large hospital dataset [Massachusetts General Brigham Biobank (MGBB)]. All recalled participants underwent medical history, physical exam, completed detailed questionnaires and laboratory evaluation including a frequently sampled intravenous glucose tolerance test. Continuous and categorical variables were analyzed with a t-test/non-parametric Wilcoxon rank sum test and a Fisher's exact test, respectively. Twenty-five rare PROKR2 variant carriers (11 males and 14 females, mean age 45.6 years ± SD 11.7) and 24 non-carrier controls (16 males and 8 females, mean age 44.8 years ± SD 10) were recruited. Male variant carriers were more likely to seek fertility evaluation compared to non-carrier controls (p = 0.03) and carriers of the founder PROKR2 (p.L173R) variant (44% of the cohort) in both sexes were more likely to be diagnosed with lower gastrointestinal phenotypes compared to controls (p = 0.02). This novel clinical association is in line with the reported role of prokineticin 2 in intestinal smooth muscle function in preclinical models. Rare heterozygous PROK2/R2 variants contribute to known reproductive and novel gastrointestinal phenotypes within a hospital-based population cohort.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266055","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}

引用次数: 0

Is cross-border transfer of China's human genetic data an impossible mission? 中国人类基因数据的跨境转移是不可能完成的任务吗？

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-09 DOI: 10.1007/s00439-025-02756-8

Jiajv Chen, Wei Li

{"title":"Is cross-border transfer of China's human genetic data an impossible mission?","authors":"Jiajv Chen, Wei Li","doi":"10.1007/s00439-025-02756-8","DOIUrl":"https://doi.org/10.1007/s00439-025-02756-8","url":null,"abstract":"Cross-border transfer of human genetic data is a crucial prerequisite for sharing such data globally. However, given the unique nature of human genetic data, this aspiration may not be easily realized. China, a country rich in biological resources, possesses a vast wealth of human genetic data. However, due to China's domestic laws and policies, human genetic data is considered both personal information, subject to regulations like the Personal Information Protection Law, and human genetic resources, governed by the Regulations on Management of Human Genetic Resources. This dual nature necessitates a double security review of human genetic data for cross-border transfer, rendering cross-border transfer of China's human genetic data a seemingly impossible mission. However, in recent years, China has refined its security review rules for cross-border data transfer to increase transparency and, in practice, has eased review criteria, issuing numerous administrative licenses. Such a shift of stance is not fortuitous but rather a planned and purposeful reflection of China's top-level design to promote self-reliance and self-improvement in science and technology, as well as its strategic goal of joining international digital economy organizations.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247671","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}

引用次数: 0

Harnessing genotype and phenotype data for population-scale variant classification using large language models and bayesian inference. 利用大语言模型和贝叶斯推理，利用基因型和表型数据进行种群尺度的变异分类。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-01 Epub Date: 2025-04-23 DOI: 10.1007/s00439-025-02743-z

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

{"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":"10.1007/s00439-025-02743-z","url":null,"abstract":"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.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"605-614"},"PeriodicalIF":3.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170740/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome-wide association study of Fuchs' endothelial corneal dystrophy in the German population. 德国人群中Fuchs角膜内皮营养不良的全基因组关联研究。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-01 Epub Date: 2025-05-12 DOI: 10.1007/s00439-025-02749-7

Juliane Fechner, Guilherme B Neumann, Fabia Murza, Leonard Matthias, Marcus Walckling, Claudia Brockmann, Thomas A Fuchsluger, Tobias Brockmann

{"title":"Genome-wide association study of Fuchs' endothelial corneal dystrophy in the German population.","authors":"Juliane Fechner, Guilherme B Neumann, Fabia Murza, Leonard Matthias, Marcus Walckling, Claudia Brockmann, Thomas A Fuchsluger, Tobias Brockmann","doi":"10.1007/s00439-025-02749-7","DOIUrl":"10.1007/s00439-025-02749-7","url":null,"abstract":"The genetic etiology of Fuchs Endothelial Corneal Dystrophy (FECD) is not yet fully elucidated. While the disease is widespread and the leading indication for corneal transplantation in the Western world, the concurrent shortage of corneal transplants underscores the urgent need for further research into the underlying mechanisms. Such investigations could enable the development of innovative therapeutic strategies. Therefore, we aimed to verify candidate genes previously identified and sought after novel variants in the German population. Undertaking a genome wide association study (GWAS) using the Axiom™ Precision Medicine Diversity Array on 157 FECD cases and 309 controls, followed by pathway enrichment analysis, we were able to confirm the significance of the TCF4 locus (rs613872, p = 8.0 × 10- 23, OR = 8.60, h2 = 0.72) and identified a range of novel variants. Further fine-mapping highlighted novel candidate SNPs, such as on chromosome 5 in the SEMA6A gene (rs153643, p = 3.1 × 10- 9, OR = 2.75, h2 = 0.30), and on chromosome 19 in the DNAJC19P3 gene (rs62117964, p = 3.3 × 10- 8, OR = 3.61, h2 = 0.29). SEMA6A gene is involved in apoptotic pathways and cytoskeletal remodeling, making it an interesting candidate gene for further investigations as a potential therapeutic target. Furthermore, several variants were identified in lncRNAs, which presumably influence the expression of nearby protein-coding genes. For example, LOC105372130, which is associated with corneal hysteresis and corneal resistance factor, may influence the expression of TCF4.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"653-664"},"PeriodicalIF":3.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989880","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}

引用次数: 0

Understanding the genetic architecture and phenotypic landscape of SPTB gene variants causing hereditary spherocytosis in an Indian cohort. 了解SPTB基因变异导致遗传性球形红细胞增多症的遗传结构和表型景观在印度队列。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-01 Epub Date: 2025-05-06 DOI: 10.1007/s00439-025-02748-8

Tejashree Anil More, Prabhakar Kedar

{"title":"Understanding the genetic architecture and phenotypic landscape of SPTB gene variants causing hereditary spherocytosis in an Indian cohort.","authors":"Tejashree Anil More, Prabhakar Kedar","doi":"10.1007/s00439-025-02748-8","DOIUrl":"10.1007/s00439-025-02748-8","url":null,"abstract":"Hereditary spherocytosis (HS) is a common form of haemolytic anaemia caused by defects or deficiencies in genes encoding erythrocyte membrane proteins, such as ANK1, SPTB, SLC4A1, EPB42, and SPTA1. Among these, ANK1 and SPTB mutations are the most frequent causes of HS worldwide. This study analysed 53 Indian HS patients, identifying 33 novel and 12 previously reported SPTB variants using targeted next-generation sequencing (t-NGS). The identified SPTB variants included frameshift (28%), missense (24%), nonsense (44%), and splicing (4%) types, with nonsense variants being the most common. These nonsense variants typically result in truncated proteins. The variants were widely distributed across the gene, with the highest density observed in the spectrin repeats and ankyrin-binding domain, while no variants were found in the tetramerization domain. All identified SPTB variants exhibited heterozygous inheritance, consistent with an autosomal dominant inheritance pattern of the gene causing HS. One patient, however, carried compound heterozygous variants, leading to severe anaemia, and five patients had de novo SPTB variants. This study expands the spectrum of SPTB variants, enhances the understanding of spectrin-related molecular defects, establishes genotype-phenotype correlations, and provides valuable insights for laboratories developing genetic tests for HS. The high number of identified variants highlights the importance of advanced technologies like NGS for accurate molecular diagnosis in HS disorder. This approach not only supports clinical diagnostics but also aids in family counseling for improved management of HS.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"633-651"},"PeriodicalIF":3.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981872","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}

引用次数: 0

Exploring mutation carriers' preferences regarding onset and progression of disease predictions for adult-onset genetic neurodegenerative diseases: a qualitative interview study. 探索突变携带者对成人发病遗传性神经退行性疾病的发病和疾病预测进展的偏好：一项定性访谈研究。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-06-01 Epub Date: 2025-05-26 DOI: 10.1007/s00439-025-02750-0

Max J Rensink, M H N Schermer, A Tibben, E K Bijlsma, S T de Bot, J A Kievit, L L E Bolt

{"title":"Exploring mutation carriers' preferences regarding onset and progression of disease predictions for adult-onset genetic neurodegenerative diseases: a qualitative interview study.","authors":"Max J Rensink, M H N Schermer, A Tibben, E K Bijlsma, S T de Bot, J A Kievit, L L E Bolt","doi":"10.1007/s00439-025-02750-0","DOIUrl":"10.1007/s00439-025-02750-0","url":null,"abstract":"Currently, new research projects aim to develop prognostic models that more accurately predict the age of onset and progression of disease for adult-onset autosomal dominant neurodegenerative diseases that lack disease-modifying treatments. While such predictions can be important for medical research and valuable in clinical practice, the perspectives of mutation carriers on receiving onset and progression predictions have not yet been explored. In this Dutch qualitative interview study, conducted between May and August 2023, the preferences, views, and concerns of 25 asymptomatic mutation carriers of Huntington's Disease, Spinocerebellar Ataxia type 1, or Spinocerebellar Ataxia type 3 regarding onset and progression predictions were examined. Reasons for wanting to receive onset and progression predictions included life planning, preparing for the disease, informing family members, and reducing uncertainty and hypervigilance. Reasons against included concerns about negative psychological effects, the expectation of similar disease progression as family members, and a preference for receiving progression information at a later stage. Most participants were open towards disclosure of onset predictions but more hesitant regarding receiving progression information. The reasons expressed and the preferred predicted age ranges varied among age groups, and some differences in preferences were observed between the three diseases. These findings may guide the development and responsible implementation of such prognostic models and can support healthcare professionals in the counselling of mutation carriers of adult-onset genetic neurodegenerative diseases.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"665-677"},"PeriodicalIF":3.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142375","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}

引用次数: 0