Human Genomics最新文献

{"title":"Genetic variants of m¹A modification genes and the risk of neuroblastoma: novel insights from a Chinese case-control study.","authors":"Jiaming Chang, Lei Lin, Wenli Zhang, Jiliang Yang, Mengzhen Zhang, Huimin Yin, Xinxin Zhang, Chunlei Zhou, Yan Zou, Jing He","doi":"10.1186/s40246-025-00767-0","DOIUrl":"https://doi.org/10.1186/s40246-025-00767-0","url":null,"abstract":"<p><strong>Background: </strong>The N¹-adenosine methylation (m¹A) modification plays a significant role in various cancers. However, the functions of m¹A modification genes and their variants in neuroblastoma remain to be elucidated.</p><p><strong>Methods: </strong>We conducted a case-control study involving 402 neuroblastoma patients and 473 cancer-free controls from China via the TaqMan genotyping method to evaluate m¹A modification gene polymorphisms. Multivariate logistic regression analysis was conducted to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Additionally, expression quantitative trait locus (eQTL) analysis utilizing the Genotype-Tissue Expression database was performed to investigate the impacts of significant polymorphisms on gene expression. The relationships between gene expression and the risk and prognosis of neuroblastoma patients were further examined via publicly available datasets by using the R2 platform.</p><p><strong>Results: </strong>We found that TRMT10C rs4618204 C > T significantly decreased neuroblastoma risk (CT/TT vs. CC: adjusted OR = 0.74, 95% CI = 0.56-0.97, P = 0.030). Moreover, polymorphisms of the TRMT10C (rs3762735), TRMT6 (rs451571 and rs236110), and ALKBH3 (rs10768993 and rs2292889) genes were associated with neuroblastoma risk in specific subgroups. Complete linkage disequilibrium and eQTL analysis revealed a significant association between rs4618204 C > T and reduced expression of the TRMT10C gene. Additionally, higher expression levels of the TRMT10C gene were observed to be linked to increased risk, malignancy, and poorer prognosis in neuroblastoma patients.</p><p><strong>Conclusions: </strong>TRMT10C rs4618204 C > T was demonstrated to be significantly associated with an increased risk of neuroblastoma and may serve as a potential molecular marker for early diagnosis. Further studies are warranted to fully elucidate the specific molecular mechanisms involved in this effect.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"50"},"PeriodicalIF":3.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome.","authors":"Belén García-Bohórquez, Purificación Marín-Reina, Elena Aller, Pilar Barberán-Martínez, Miguel Armengot, Roberto Llorens-Salvador, Inmaculada Concepción Almor-Palacios, José M Millán, Gema García-García","doi":"10.1186/s40246-025-00759-0","DOIUrl":"https://doi.org/10.1186/s40246-025-00759-0","url":null,"abstract":"<p><strong>Background: </strong>Ciliopathies are characterized by the dysfunction of cilia, being inherited retinal dystrophies (IRDs) included in sensory ciliopathies. Besides, oro-facial-digital syndrome (OFD) is caused by mutations in ciliary genes, leading to dysmorphic features. Mutations in TBC1D32 were associated to retinal dystrophy and OFD, defining this form as OFD-IX.</p><p><strong>Results: </strong>A clinical exome analysis performed on a patient presenting with OFD-IX and sensorineural hearing loss (SNHL) identified two variants in TBC1D32, one of which affects splicing, with its impact validated using a minigene assay.</p><p><strong>Conclusions: </strong>These results suggest that SNHL may represent a new clinical feature associated with this gene.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"49"},"PeriodicalIF":3.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing translational exposomics: bridging genome, exposome and personalized medicine.","authors":"Dimosthenis Sarigiannis, Spyros Karakitsios, Ourania Anesti, Arthur Stem, Damaskini Valvi, Susan C J Sumner, Leda Chatzi, Michael P Snyder, David C Thompson, Vasilis Vasiliou","doi":"10.1186/s40246-025-00761-6","DOIUrl":"https://doi.org/10.1186/s40246-025-00761-6","url":null,"abstract":"<p><p>Understanding the interplay between genetic predisposition and environmental and lifestyle exposures is essential for advancing precision medicine and public health. The exposome, defined as the sum of all environmental exposures an individual encounters throughout their lifetime, complements genomic data by elucidating how external and internal exposure factors influence health outcomes. This treatise highlights the emerging discipline of translational exposomics that integrates exposomics and genomics, offering a comprehensive approach to decipher the complex relationships between environmental and lifestyle exposures, genetic variability, and disease phenotypes. We highlight cutting-edge methodologies, including multi-omics technologies, exposome-wide association studies (EWAS), physiology-based biokinetic modeling, and advanced bioinformatics approaches. These tools enable precise characterization of both the external and the internal exposome, facilitating the identification of biomarkers, exposure-response relationships, and disease prediction and mechanisms. We also consider the importance of addressing socio-economic, demographic, and gender disparities in environmental health research. We emphasize how exposome data can contextualize genomic variation and enhance causal inference, especially in studies of vulnerable populations and complex diseases. By showcasing concrete examples and proposing integrative platforms for translational exposomics, this work underscores the critical need to bridge genomics and exposomics to enable precision prevention, risk stratification, and public health decision-making. This integrative approach offers a new paradigm for understanding health and disease beyond genetics alone.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"48"},"PeriodicalIF":3.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and clinical aspects of histone-related disorders.","authors":"Mode Al Ojaimi, Bashar J Banimortada, Abduljalil Alragheb, Razan S Hajir, Carolina Alves, Duaa Walid, Afsheen Raza, Ayman W El-Hattab","doi":"10.1186/s40246-025-00734-9","DOIUrl":"https://doi.org/10.1186/s40246-025-00734-9","url":null,"abstract":"<p><p>Epigenetics is the coordination of gene expression without alterations in the DNA sequence. Epigenetic gene expression is regulated by an intricate system that revolves around the interaction of histone proteins and DNA within the chromatin structure. Histones remain at the core of the epigenetic gene transcription regulation where histone proteins, along with the histone modification enzymes, and the subunits of chromatin remodelers and epigenetic readers play essential roles in regulating gene expression. Histone-related disorders encompass the syndromes induced by pathogenic variants in genes encoding histones, genes encoding histone modification enzymes, and genes encoding subunits of chromatin remodeler and epigenetic reader complexes. Defects in genes encoding histones lead to the expression of abnormal histone proteins. Abnormalities in genes encoding histone modification enzymes result in aberrant histone modifications. Defects in genes encoding subunits of the chromatin remodeler complexes result in defective chromatin remodeling. Defects in genes that code for the epigenetic readers (bromodomain proteins) will hinder their ability to regulate gene transcription. These disorders typically present manifestations that impact the nervous system which is particularly sensitive due to its need for specific patterns of gene expression for neural cell function and differentiation. To date, 72 histone-related disorders have been described including 7 syndromes due to defects in histone genes, 35 syndromes due to histone modifications defects, 26 syndromes due to defects in chromatin remodeling, and 4 due to defects in epigenetic readers. In this review article, the molecular basis of histone structure and function is first explained, followed by a summary of the histone-related syndromes.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"47"},"PeriodicalIF":3.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional analyses of splice site variants in TCF12.","authors":"Angela Borst, Tilmann Schweitzer, Denise Horn, Erdmute Kunstmann, Eva-Maria König, Natalie Pluta, Eva Klopocki","doi":"10.1186/s40246-025-00758-1","DOIUrl":"https://doi.org/10.1186/s40246-025-00758-1","url":null,"abstract":"<p><p>Pre-mRNA splicing is a fundamental step in protein synthesis within a cell. Malfunctions during this process can lead to dysfunctional proteins and thus, to a variety of different human diseases. Mis-splicing can be caused by genetic variants influencing many different molecular processes, e.g. splice donor and splice acceptor site variants. Today, the consequences of these variants can be calculated via different in-silico programs. Due to the complexity of the splicing process, however, these predictions are not always correct and should not be used as stand-alone criteria for the classification of potentially disease-causing variants. Therefore, in case RNA from an appropriate tissue is not available additional in-vitro studies, such as a minigene splice assay, which allows functional analyses of potentially disease-causing variants, are necessary to demonstrate an effect on splicing. One example of a human developmental disorder occasionally caused by mis-splicing of transcripts is craniosynostosis. This congenital disorder is defined by the premature fusion of one or multiple cranial sutures in the neurocranium. To date, numerous mutation types in more than 50 genes which are involved in a broad range of different cellular functions and pathways have been associated with craniosynostosis. For instance, the TCF12 gene encoding the bHLH (basic helix-loop-helix) protein TCF12 (transcription factor 12) is linked to Craniosynostosis 3 (OMIM: 615314) which exhibits a Saethre-Chotzen (OMIM:101400) like phenotype. In this study, we report a pipeline for functional validation of potential splice site altering variants. First, we describe the identification of two novel genetic variants and revalidation of one previously described genetic variant in patients with craniosynostosis. According to in-silico predictions, the splicing of the corresponding transcripts is altered, and the variants are potentially disease causing. We subsequently classify the consequences of alterations in TCF12 experimentally. The suspected aberrant splicing was investigated via an in-vitro minigene splice assay. In two out of three variants, the in-silico prediction and in-vitro experiments were consistent. In all variants a significantly reduced transcriptional activity was demonstrated. In summary, the combination of in-silico prediction and functional assays allowed us to classify the variants as likely pathogenic without the need for additional patient material.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"45"},"PeriodicalIF":3.8,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of concern for global biomedical research by the human genome organization (HUGO).","authors":"Ada Hamosh, Fabiana Arzuaga, Karen B Avraham, Zilfalil Bin Alwi, Anne Bowcock, Sir John Burn, Piero Carninci, Collet Dandara, Iscia Lopes-Cendes, Leon Mutesa, Partha P Majumder, Juergen K V Reichardt, Joris A Veltman","doi":"10.1186/s40246-025-00755-4","DOIUrl":"https://doi.org/10.1186/s40246-025-00755-4","url":null,"abstract":"<p><p>Cuts to US science funding will stall advances in genomics affecting public health, rare disease and cancer diagnostics and therapeutics in the US and around the world.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"46"},"PeriodicalIF":3.8,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenomic insights into atorvastatin and rosuvastatin adverse effects: a prospective observational study in the UAE's multiethnic population.","authors":"Mais N Alqasrawi, Zeina N Al-Mahayri, Areej S AlBawa'neh, Lubna Q Khasawneh, Lilas Dabaghie, Sahar M Altoum, Dana Hamza, Virendra Misra, Husam Ouda, Salahdein Aburuz, Fatima Al-Maskari, Juma AlKaabi, George P Patrinos, Bassam R Ali","doi":"10.1186/s40246-025-00753-6","DOIUrl":"https://doi.org/10.1186/s40246-025-00753-6","url":null,"abstract":"<p><strong>Background: </strong>Statins are essential for managing cardiovascular disease (CVD), but adverse effects often lead to treatment discontinuation and non-adherence, underscoring the need for personalized approaches. This study aimed to evaluate the influence of pharmacogenomic (PGx) variants and demographic factors on statin-associated adverse effects in a multiethnic cohort from the United Arab Emirates (UAE).</p><p><strong>Methods: </strong>This sub-analysis of the EmHeart Study included 675 patients using rosuvastatin or atorvastatin. Patients were genotyped for SLCO1B1 and ABCG2 actionable variants using real-time PCR. Data on demographics, comorbidities, and statin use were extracted from electronic health records. Adverse events, including statin-associated muscle symptoms (SAMS) and liver enzyme elevation, were tracked over 12 months. Associations were analyzed using chi-square tests and logistic regression.</p><p><strong>Results: </strong>Rosuvastatin users carrying the ABCG2 rs2231142 variant had a threefold increased risk of liver enzyme elevation, particularly among East Asian patients (P < 0.005). Atorvastatin users with the SLCO1B1 rs4149056 variant exhibited a twofold increased risk of SAMS, with higher rates observed in females and Arabs (P < 0.05). The combination of rosuvastatin with ezetimibe further exacerbated risks of SAMS and liver enzyme elevation.</p><p><strong>Conclusion: </strong>This study highlights the importance of genetic testing and demographic factors, such as ethnicity and gender, in tailoring statin therapy to minimize adverse effects. Despite extensive research on PGx-guided statin prescribing, clinical implementation remains limited. Integrating PGx testing into routine practice and enhancing physician awareness of genetic and demographic risk factors can improve the safety, efficacy, and adherence of lipid-lowering therapies in diverse populations.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"44"},"PeriodicalIF":3.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the causal effects of type 2 diabetes and obesity-related traits on COVID-19 severity.","authors":"Jieun Seo, Gaeun Kim, Seunghwan Park, Aeyeon Lee, Liming Liang, Taesung Park, Wonil Chung","doi":"10.1186/s40246-025-00747-4","DOIUrl":"https://doi.org/10.1186/s40246-025-00747-4","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes (T2D) and obesity-related traits are highly comorbid with coronavirus disease 2019 (COVID-19), but their causal relationships with disease severity remain unclear. While recent Mendelian randomization (MR) studies suggest a causal link between obesity-related traits and COVID-19 severity, findings regarding T2D are inconsistent, particularly when adjusting for body mass index (BMI). This study aims to clarify these relationships.</p><p><strong>Methods: </strong>We applied various MR methods to assess the causal effects of BMI-adjusted T2D (T2DadjBMI) and obesity-related traits (BMI, waist circumference, and waist-hip ratio) on COVID-19 severity. Genetic instruments were obtained from large-scale genome-wide association studies (GWAS), including 898K participants for T2D and 2M for COVID-19 severity. To address potential bias from sample overlap, we conducted large-scale simulations comparing MR results from overlapping and independent samples.</p><p><strong>Results: </strong>Our MR analysis identified a significant causal relationship between T2DadjBMI and increased COVID-19 severity (OR = 1.057, 95% CI = 1.012-1.105). Obesity-related traits were also causally associated with COVID-19 severity. Simulations confirmed that MR results remained robust to sample overlap, demonstrating consistency between overlapping and independent datasets.</p><p><strong>Conclusions: </strong>These findings highlight the causal role of T2D and obesity-related traits in COVID-19 severity, emphasizing the need for targeted prevention and management strategies for high-risk populations. The robustness of our MR analysis, even in the presence of sample overlap, strengthens the reliability of these causal inferences.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"43"},"PeriodicalIF":3.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular genetic testing and cohort analysis of 32 twin pairs with neurodevelopmental disorders-Reporting a novel de novo variant of TET3.","authors":"Lianni Mei, Chunchun Hu, Guangbo Jin, Chuanhui Ge, Yiting Zhu, Dongyun Li, Wenzhu Peng, Huiping Li, Xiu Xu, Yan Jiang, Guoliang Xu, Qiong Xu","doi":"10.1186/s40246-025-00748-3","DOIUrl":"https://doi.org/10.1186/s40246-025-00748-3","url":null,"abstract":"<p><p>Neurodevelopmental disorders (NDDs) pose significant challenges due to their impact on cognitive, social and motor abilities, often rooted in genetic factors such as copy number variations (CNVs) and single nucleotide variantions (SNVs). Molecular genetic testing, advanced due to sequencing technologies, is instrumental in diagnosing NDDs, with twins offering unique perspectives in detecting novel de novo CNVs and SNVs. The study enrolled 32 pairs of twins that underwent molecular genetic testing and comprehensive clinical data collection. Additionally, we analyzed the potential deleterious effects of a novel de novo TET methylcytosine dioxygenase 3 (TET3) variant (c.4927G > A) using western blotting, immunofluorescence assay and enzymatic activity assay. Analyzing simultaneously, the overall detection yield of molecular genetic testing was 17.2% (11/64). Children with disease-related genetic variants had lower total developmental quotients (DQ) than children without disease-related genetic variants. One pair of monozygotic twins carried a novel de novo TET3 variant. Immunostaining assay revealed that while the wildtype TET3 protein was evenly distributed in the nucleus, the variant was concentrated around the nucleus. Anenzymatic assay using corresponding TET2 mutants suggested that the variant has a significantly reduced activity. Taken together, our study elaborated molecular genetic testing results of 32 pairs of twins and found that children with lower developmental levels are prone to possessing identifiable genetic variants. We reported the clinical phenotype of a pair of monozygotic twins carrying a novel de novo TET3 variant and confirmed the detrimental effects of this variant in vitro.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"42"},"PeriodicalIF":3.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional analysis of a novel FOXL2 mutation in blepharophimosis, ptosis, and epicanthus inversus syndrome type II and elucidation of the genotype-phenotype correlation.","authors":"Bingyan Shen, Xi Chen, Xiuying Zhu, Ziwen Chen, Yenan Fang, Qin Dai, Xinyu Li, Qiqi Xie, Wencan Wu, Min Wang","doi":"10.1186/s40246-025-00752-7","DOIUrl":"https://doi.org/10.1186/s40246-025-00752-7","url":null,"abstract":"<p><strong>Background: </strong>Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder caused by genetic mutations. However, the genotype-phenotype correlation remains unclear. This study aimed to identify mutations in a Chinese family with BPES and elucidate the genotype-phenotype relationship.</p><p><strong>Methods: </strong>A comprehensive clinical and molecular genetic analysis was conducted on a three-generation Chinese family with BPES, which was prospectively enrolled at the Eye Hospital of Wenzhou Medical University. Affected individuals underwent systematic phenotyping, including detailed physical and ophthalmic evaluations. Genomic DNA was isolated from peripheral blood samples and subjected to whole-exome sequencing, followed by targeted Sanger sequencing for variant validation. Candidate disease-associated variants were analyzed using in silico predictive algorithms to assess their potential structural and functional impact on encoded proteins. To further elucidate the pathogenicity of the identified mutation, functional studies were performed, including immunofluorescence-based subcellular localization assays and quantitative real-time PCR to evaluate transcriptional regulatory effects.</p><p><strong>Results: </strong>Six affected individuals of this pedigree presented with canonical BPES features including small palpebral fissures, ptosis, epicanthus inversus, and telecanthus, without premature ovarian failure, consistent with a diagnosis of BPES type II. Whole-exome sequencing revealed a heterozygous missense mutation (c.313 A > C:p.N105H) in FOXL2, which was subsequently validated by Sanger sequencing. This variant demonstrated complete cosegregation with the BPES phenotype across all affected family members. According to ACMG guidelines, the variant was classified as Likely Pathogenic (PS1 + PM1 + PM2 + PP3). In silico pathogenicity prediction tools classified the p.N105H variant as deleterious. Immunofluorescence assays revealed aberrant nuclear aggregation of the mutant FOXL2 protein, and functional characterization via quantitative real-time PCR demonstrated no significant dysregulation (P > 0.05) of downstream targets (STAR, OSR2).</p><p><strong>Conclusions: </strong>This study provides functional evidence of the pathogenic FOXL2 mutation (c.313 A > C, p.N105H) in BPES type II, demonstrating its disruptive effects on protein localization while maintaining normal transcriptional activity of downstream targets. These findings expand the mutational spectrum of FOXL2 related disorders and enhance our understanding of genotype-phenotype correlations in BPES.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"41"},"PeriodicalIF":3.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}