Human Genetics最新文献

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 : 2025-07-01 Epub 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":"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":"761-773"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","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

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-07-01 Epub Date: 2025-05-27 DOI: 10.1007/s00439-025-02753-x

Shangdi Zhang, Kewei Du, Shan Gao, Zejing Liu, Linmei Chen, Xue Wu, Linjing Li

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 : 2025-07-01 Epub 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":"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":"695-713"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","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

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 : 2025-07-01 Epub 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":"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":"715-725"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","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

Whole genome sequencing identifies monogenic disease in 56.1% of families with early-onset steroid-resistant nephrotic syndrome. 全基因组测序确定56.1%的早发性类固醇抵抗性肾病综合征家庭存在单基因疾病。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-07-01 Epub Date: 2025-05-22 DOI: 10.1007/s00439-025-02752-y

Neveen A Soliman, Mohamed A Elmonem, Ahmed F El-Sayed, Eman Ramadan, Ahmed M Badr, Fatma M Atia, Rasha Helmy, May O Amer, Ahmed Abd El-Raouf, Fadya M El-Garhy, Omnia M Abdel-Haseb, Tokka M Hassan, Yasmeen K Farouk, Ahmed El-Hosseiny, Usama Bakry, Asmaa Ali, Sheri Saleeb, Tasnim A Ghanim, Mahynour Albarbary, Ahmed Elmahy, Tarek Elnagdy, Amira Ragheb, Wael A Hassan, Ahmed Moustafa, Khaled Amer

{"title":"Whole genome sequencing identifies monogenic disease in 56.1% of families with early-onset steroid-resistant nephrotic syndrome.","authors":"Neveen A Soliman, Mohamed A Elmonem, Ahmed F El-Sayed, Eman Ramadan, Ahmed M Badr, Fatma M Atia, Rasha Helmy, May O Amer, Ahmed Abd El-Raouf, Fadya M El-Garhy, Omnia M Abdel-Haseb, Tokka M Hassan, Yasmeen K Farouk, Ahmed El-Hosseiny, Usama Bakry, Asmaa Ali, Sheri Saleeb, Tasnim A Ghanim, Mahynour Albarbary, Ahmed Elmahy, Tarek Elnagdy, Amira Ragheb, Wael A Hassan, Ahmed Moustafa, Khaled Amer","doi":"10.1007/s00439-025-02752-y","DOIUrl":"10.1007/s00439-025-02752-y","url":null,"abstract":"Genetic causes of steroid-resistant-nephrotic-syndrome (SRNS) represent a rapidly growing number of monogenic diseases. The reported diagnostic yield of various studies applying genetic panels and exome-sequencing to diagnose SRNS is usually < 30%. We performed genome-sequencing in a cohort of Egyptian SRNS patients. We recruited 47 SRNS patients belonging to 41 unrelated families [28 males/19 females; median (range): 6 (0.5-22 years)]. We established a pipeline for genome sequencing, bioinformatics analysis, variant curation and protein modeling at the Egypt Center for Research and Regenerative Medicine (ECRRM). Disease-causing variants were detected in 27/47 patients (57.4%) belonging to 23/41 families (56.1%), including nine novel variants in NPHS1, NPHS2, COL4A3, MYO1E, NUP93, PLCE1, PODXL, SMARCAL1 and WT1. Novel variants were confirmed by Sanger sequencing and were segregated in families of affected patients. NPHS2 was the most common causative gene in 8/23 (34.8%) of confirmed families, followed by NPHS1, WT1, and SMARCAL1 in 2/23 families (8.7%) each. All detected missense variants were evaluated through protein modeling and were predicted deleterious. Our study expanded the spectrum of SRNS disease-causing variants and revealed a monogenic cause in 56.1% of investigated families. In our cohort, no deep intronic or regulatory variants were detected by genome-sequencing. Pursuing genetic diagnosis in SRNS patients is crucial to inform clinical decision making, genetic counseling, transplantation strategy and prenatal diagnosis thus improving clinical outcome of affected patients.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"727-740"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119632","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

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 : 2025-07-01 Epub 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":"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":"775-794"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","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

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

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